The DA antagonist tiapride impairs context-related extinction learning in a novel context without affecting renewal

PubMed Central

Lissek, Silke; Glaubitz, Benjamin; Wolf, Oliver T.; Tegenthoff, Martin

2015-01-01

Renewal describes the recovery of an extinguished response if recall is tested in a context different from the extinction context. Behavioral studies demonstrated that attention to relevant context strengthens renewal. Neurotransmitters mediating attention and learning such as the dopaminergic (DA) system presumably modulate extinction learning and renewal. However, the role of DA for non-fear-based extinction learning and renewal in humans has not yet been investigated. This fMRI study investigated effects of DA-antagonism upon context-related extinction in a predictive learning task in which extinction occurred either in a novel (ABA) or an unchanged (AAA) context. The tiapride-treated group (TIA) showed significantly impaired ABA extinction learning and a significant within-group difference between ABA and AAA extinction, compared to placebo (PLAC). Groups did not differ in their level of ABA renewal. In ABA extinction, TIA showed reduced activation in dlPFC and OFC, hippocampus, and temporal regions. Across groups, activation in PFC and hippocampus correlated negatively with ABA extinction errors. Results suggest that in context-related extinction learning DA in PFC and hippocampus is involved in readjusting the cue-outcome relationship in the presence of a novel context. However, relating context to the appropriate association during recall does not appear to rely exclusively on DA signaling. PMID:26388752

Enhancing Effects of NMDA-Receptor Blockade on Extinction Learning and Related Brain Activation Are Modulated by BMI

PubMed Central

Golisch, Anne; Heba, Stefanie; Glaubitz, Benjamin; Tegenthoff, Martin; Lissek, Silke

2017-01-01

A distributed network including prefrontal and hippocampal regions is involved in context-related extinction learning as well as in renewal. Renewal describes the recovery of an extinguished response if the context of extinction differs from the context of recall. Animal studies have demonstrated that prefrontal, but not hippocampal N-methyl-D-aspartate receptor (NMDAR) antagonism disrupted extinction learning and processing of task context. However, human studies of NMDAR in extinction learning are lacking, while NMDAR antagonism yielded contradictory results in other learning tasks. This fMRI study investigated the role of NMDAR for human behavioral and brain activation correlates of extinction and renewal. Healthy volunteers received a single dose of the NMDAR antagonist memantine prior to extinction of previously acquired stimulus-outcome associations presented in either identical or novel contexts. We observed better, and partly faster, extinction learning in participants receiving the NMDAR antagonist compared to placebo. However, memantine did not affect renewal. In both extinction and recall, the memantine group showed a deactivation in extinction-related brain regions, particularly in the prefrontal cortex, while hippocampal activity was increased. This higher hippocampal activation was in turn associated with the participants' body mass index (BMI) and extinction errors. Our results demonstrate potentially dose-related enhancing effects of memantine and highlight involvement of hippocampal NMDAR in context-related extinction learning. PMID:28326025

Reconciling Reinforcement Learning Models with Behavioral Extinction and Renewal: Implications for Addiction, Relapse, and Problem Gambling

ERIC Educational Resources Information Center

Redish, A. David; Jensen, Steve; Johnson, Adam; Kurth-Nelson, Zeb

2007-01-01

Because learned associations are quickly renewed following extinction, the extinction process must include processes other than unlearning. However, reinforcement learning models, such as the temporal difference reinforcement learning (TDRL) model, treat extinction as an unlearning of associated value and are thus unable to capture renewal. TDRL…

Stress-enhanced fear learning in rats is resistant to the effects of immediate massed extinction

PubMed Central

Long, Virginia A.; Fanselow, Michael S.

2014-01-01

Enhanced fear learning occurs subsequent to traumatic or stressful events and is a persistent challenge to the treatment of post-traumatic stress disorder (PTSD). Facilitation of learning produced by prior stress can elicit an exaggerated fear response to a minimally aversive event or stimulus. Stress-enhanced fear learning (SEFL) is a rat model of PTSD; rats previously exposed to the SEFL 15 electrical shocks procedure exhibit several behavioral responses similar to those seen in patients with PTSD. However, past reports found that SEFL is not mitigated by extinction (a model of exposure therapy) when the spaced extinction began 24 h after stress. Recent studies found that extinction from 10 min to 1 h subsequent to fear conditioning “erased” learning, whereas later extinction, occurring from 24 to 72 h after conditioning did not. Other studies indicate that massed extinction is more effective than spaced procedures. Therefore, we examined the time-dependent nature of extinction on the stress-induced enhancement of fear learning using a massed trial’s procedure. Experimental rats received 15 foot shocks and were given either no extinction or massed extinction 10 min or 72 h later. Our present data indicate that SEFL, following traumatic stress, is resistant to immediate massed extinction. Experimental rats showed exaggerated new fear learning regardless of when extinction training occurred. Thus, post-traumatic reactivity such as SEFL does not seem responsive to extinction treatments. PMID:22176467

Sex differences in learned fear expression and extinction involve altered gamma oscillations in medial prefrontal cortex.

PubMed

Fenton, Georgina E; Halliday, David M; Mason, Rob; Bredy, Timothy W; Stevenson, Carl W

2016-11-01

Sex differences in learned fear expression and extinction involve the medial prefrontal cortex (mPFC). We recently demonstrated that enhanced learned fear expression during auditory fear extinction and its recall is linked to persistent theta activation in the prelimbic (PL) but not infralimbic (IL) cortex of female rats. Emerging evidence indicates that gamma oscillations in mPFC are also implicated in the expression and extinction of learned fear. Therefore we re-examined our in vivo electrophysiology data and found that females showed persistent PL gamma activation during extinction and a failure of IL gamma activation during extinction recall. Altered prefrontal gamma oscillations thus accompany sex differences in learned fear expression and its extinction. These findings are relevant for understanding the neural basis of post-traumatic stress disorder, which is more prevalent in women and involves impaired extinction and mPFC dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

Instructed fear learning, extinction, and recall: additive effects of cognitive information on emotional learning of fear.

PubMed

Javanbakht, Arash; Duval, Elizabeth R; Cisneros, Maria E; Taylor, Stephan F; Kessler, Daniel; Liberzon, Israel

2017-08-01

The effects of instruction on learning of fear and safety are rarely studied. We aimed to examine the effects of cognitive information and experience on fear learning. Fourty healthy participants, randomly assigned to three groups, went through fear conditioning, extinction learning, and extinction recall with two conditioned stimuli (CS+). Information was presented about the presence or absence of conditioned stimulus-unconditioned stimulus (CS-US) contingency at different stages of the experiment. Information about the CS-US contingency prior to fear conditioning enhanced fear response and reduced extinction recall. Information about the absence of CS-US contingency promoted extinction learning and recall, while omission of this information prior to recall resulted in fear renewal. These findings indicate that contingency information can facilitate fear expression during fear learning, and can facilitate extinction learning and recall. Information seems to function as an element of the larger context in which conditioning occurs.

Effects of activation and blockade of NMDA receptors on the extinction of a conditioned passive avoidance response in mice with different levels of anxiety.

PubMed

Tomilenko, R A; Dubrovina, N I

2007-06-01

The effects of an agonist (D-cycloserine) and an antagonist (dizocilpine) of N-methyl-D-aspartate (NMDA) receptors on the learning and extinction of a conditioned passive avoidance response were studied in mice with low, intermediate, and high levels of anxiety. In intermediate-anxiety mice, D-cycloserine (30 mg/kg) had no effect on learning but accelerated extinction, while dizocilpine (0.15 mg/kg) degraded acquisition of the reflex but delayed extinction. In high-anxiety mice, with good learning and no extinction, D-cycloserine had no effect, while dizocilpine decreased learning and facilitated retention of performance of the memory trace at the ongoing level in conditions promoting extinction. In low-anxiety mice, D-cycloserine degraded learning and accelerated extinction, while dizocilpine completely blocked learning and the retention of the passive avoidance response.

Effects of sleep on memory for conditioned fear and fear extinction

PubMed Central

Pace-Schott, Edward F.; Germain, Anne; Milad, Mohammed R.

2015-01-01

Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. REM may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep’s effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. PMID:25894546

Effects of sleep on memory for conditioned fear and fear extinction.

PubMed

Pace-Schott, Edward F; Germain, Anne; Milad, Mohammed R

2015-07-01

Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning, and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. Rapid eye movement (REM) may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction, and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep's effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Can Transcranial Direct Current Stimulation Augment Extinction of Conditioned Fear?

PubMed Central

van ’t Wout, Mascha; Mariano, Timothy Y.; Garnaat, Sarah L.; Reddy, Madhavi K.; Rasmussen, Steven A.; Greenberg, Benjamin D.

2016-01-01

Background Exposure-based therapy parallels extinction learning of conditioned fear. Prior research points to the ventromedial prefrontal cortex as a potential site for the consolidation of extinction learning and subsequent retention of extinction memory. Objective/hypothesis The present study aimed to evaluate whether the application of non-invasive transcranial direct current stimulation (tDCS) during extinction learning enhances late extinction and early recall in human participants. Methods Forty-four healthy volunteers completed a 2-day Pavlovian fear conditioning, extinction, and recall paradigm while skin conductance activity was continuously measured. Twenty-six participants received 2 mA anodal tDCS over EEG coordinate AF3 during extinction of a first conditioned stimulus. The remaining 18 participants received similar tDCS during extinction of a second conditioned stimulus. Sham stimulation was applied for the balance of extinction trials in both groups. Normalized skin conductance changes were analyzed using linear mixed models to evaluate effects of tDCS over late extinction and early recall trials. Results We observed a significant interaction between timing of tDCS during extinction blocks and changes in skin conductance reactivity over late extinction trials. These data indicate that tDCS was associated with accelerated late extinction learning of a second conditioned stimulus after tDCS was combined with extinction learning of a previous conditioned stimulus. No significant effects of tDCS timing were observed on early extinction recall. Conclusions Results could be explained by an anxiolytic aftereffect of tDCS and extend previous studies on tDCS-induced modulation of fear and threat related learning processes. These findings support further exploration of the clinical use of tDCS. PMID:27037186

Compound Stimulus Presentation Does Not Deepen Extinction in Human Causal Learning

PubMed Central

Griffiths, Oren; Holmes, Nathan; Westbrook, R. Fred

2017-01-01

Models of associative learning have proposed that cue-outcome learning critically depends on the degree of prediction error encountered during training. Two experiments examined the role of error-driven extinction learning in a human causal learning task. Target cues underwent extinction in the presence of additional cues, which differed in the degree to which they predicted the outcome, thereby manipulating outcome expectancy and, in the absence of any change in reinforcement, prediction error. These prediction error manipulations have each been shown to modulate extinction learning in aversive conditioning studies. While both manipulations resulted in increased prediction error during training, neither enhanced extinction in the present human learning task (one manipulation resulted in less extinction at test). The results are discussed with reference to the types of associations that are regulated by prediction error, the types of error terms involved in their regulation, and how these interact with parameters involved in training. PMID:28232809

Nothing is safe: Intolerance of uncertainty is associated with compromised fear extinction learning.

PubMed

Morriss, Jayne; Christakou, Anastasia; van Reekum, Carien M

2016-12-01

Extinction-resistant fear is considered to be a central feature of pathological anxiety. Here we sought to determine if individual differences in Intolerance of Uncertainty (IU), a potential risk factor for anxiety disorders, underlies compromised fear extinction. We tested this hypothesis by recording electrodermal activity in 38 healthy participants during fear acquisition and extinction. We assessed the temporality of fear extinction, by examining early and late extinction learning. During early extinction, low IU was associated with larger skin conductance responses to learned threat vs. safety cues, whereas high IU was associated with skin conductance responding to both threat and safety cues, but no cue discrimination. During late extinction, low IU showed no difference in skin conductance between learned threat and safety cues, whilst high IU predicted continued fear expression to learned threat, indexed by larger skin conductance to threat vs. safety cues. These findings suggest a critical role of uncertainty-based mechanisms in the maintenance of learned fear. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Effects of D-cycloserine on the extinction of appetitive operant learning

PubMed Central

Vurbic, Drina; Gold, Benjamin; Bouton, Mark E.

2011-01-01

Four experiments with rat subjects examined whether D-cycloserine (DCS), a partial NMDA agonist, facilitates the extinction of operant lever-pressing reinforced by food. Previous research has demonstrated that DCS facilitates extinction learning with methods that involve Pavlovian extinction. In the current experiments, operant conditioning occurred in Context A, extinction in Context B, and then testing occurred in both the extinction and conditioning contexts. Experiments 1a and 1b tested the effects of three doses of DCS (5, 15, and 30 mg/kg) on the extinction of lever pressing trained as a free operant. Experiment 2 examined their effects when extinction of the free operant was conducted in the presence of non-response-contingent deliveries of the reinforcer (which theoretically reduced the role of generalization decrement in suppressing responding). Experiment 3 examined their effects on extinction of a discriminated operant, i.e., one that had been reinforced in the presence of a discriminative stimulus, but not in its absence. A strong ABA renewal effect was observed in all four experiments during testing. However, despite the use of DCS doses and a drug administration procedure that facilitates the extinction of Pavlovian learning, there was no evidence in any experiment that DCS facilitated operant extinction learning assessed in either the extinction or the conditioning context. DCS may primarily facilitate learning processes that underlie Pavlovian, rather than purely operant, extinction. PMID:21688894

Hippocampus NMDA receptors selectively mediate latent extinction of place learning.

PubMed

Goodman, Jarid; Gabriele, Amanda; Packard, Mark G

2016-09-01

Extinction of maze learning may be achieved with or without the animal performing the previously acquired response. In typical "response extinction," animals are given the opportunity to make the previously acquired approach response toward the goal location of the maze without reinforcement. In "latent extinction," animals are not given the opportunity to make the previously acquired response and instead are confined to the previous goal location without reinforcement. Previous evidence indicates that the effectiveness of these protocols may depend on the type of memory being extinguished. Thus, one aim of the present study was to further examine the effectiveness of response and latent extinction protocols across dorsolateral striatum (DLS)-dependent response learning and hippocampus-dependent place learning tasks. In addition, previous neural inactivation experiments indicate a selective role for the hippocampus in latent extinction, but have not investigated the precise neurotransmitter mechanisms involved. Thus, the present study also examined whether latent extinction of place learning might depend on NMDA receptor activity in the hippocampus. In experiment 1, adult male Long-Evans rats were trained in a response learning task in a water plus-maze, in which animals were reinforced to make a consistent body-turn response to reach an invisible escape platform. Results indicated that response extinction, but not latent extinction, was effective at extinguishing memory in the response learning task. In experiment 2, rats were trained in a place learning task, in which animals were reinforced to approach a consistent spatial location containing the hidden escape platform. In experiment 2, animals also received intra-hippocampal infusions of the NMDA receptor antagonist 2-amino-5-phosphopentanoic acid (AP5; 5.0 or 7.5 ug/0.5 µg) or saline vehicle immediately before response or latent extinction training. Results indicated that both extinction protocols were effective at extinguishing memory in the place learning task. In addition, intra-hippocampal AP5 (7.5 µg) impaired latent extinction, but not response extinction, suggesting that hippocampal NMDA receptors are selectively involved in latent extinction. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Cannabinoid facilitation of fear extinction memory recall in humans

PubMed Central

Rabinak, Christine A.; Angstadt, Mike; Sripada, Chandra S.; Abelson, James L.; Liberzon, Israel; Milad, Mohammed R.; Phan, K. Luan

2012-01-01

A first-line approach to treat anxiety disorders is exposure-based therapy, which relies on extinction processes such as repeatedly exposing the patient to stimuli (conditioned stimuli; CS) associated with the traumatic, fear-related memory. However, a significant number of patients fail to maintain their gains, partly attributed to the fact that this inhibitory learning and its maintenance is temporary and conditioned fear responses can return. Animal studies have shown that activation of the cannabinoid system during extinction learning enhances fear extinction and its retention. Specifically, CB1 receptor agonists, such as Δ9-tetrahydrocannibinol (THC), can facilitate extinction recall by preventing recovery of extinguished fear in rats. However, this phenomenon has not been investigated in humans. We conducted a study using a randomized, double-blind, placebo-controlled, between-subjects design, coupling a standard Pavlovian fear extinction paradigm and simultaneous skin conductance response (SCR) recording with an acute pharmacological challenge with oral dronabinol (synthetic THC) or placebo (PBO) 2 hours prior to extinction learning in 29 healthy adult volunteers (THC = 14; PBO = 15) and tested extinction retention 24 hours after extinction learning. Compared to subjects that received PBO, subjects that received THC showed low SCR to a previously extinguished CS when extinction memory recall was tested 24 hours after extinction learning, suggesting that THC prevented the recovery of fear. These results provide the first evidence that pharmacological enhancement of extinction learning is feasible in humans using cannabinoid system modulators, which may thus warrant further development and clinical testing. PMID:22796109

Impaired fear extinction learning in adult heterozygous BDNF knock-out mice.

PubMed

Psotta, Laura; Lessmann, Volkmar; Endres, Thomas

2013-07-01

Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuroplasticity, which underlies learning and memory processes in different brain areas. To investigate the role of BDNF in the extinction of amygdala-dependent cued fear memories, we analyzed fear extinction learning in heterozygous BDNF knock-out mice, which possess a reduction of endogenous BDNF protein levels to ~50% of wild-type animals. Since BDNF expression has been shown to decline with aging of animals, we tested the performance in extinction learning of these mice at 2 months (young adults) and 7 months (older adults) of age. The present study shows that older adult heterozygous BDNF knock-out mice, which have a chronic 50% lack of BDNF, also possess a deficit in the acquisition of extinction memory, while extinction learning remains unaffected in young adult heterozygous BDNF knock-out mice. This deficit in extinction learning is accompanied by a reduction of BDNF protein in the hippocampus, amygdala and the prefrontal cortex. Copyright © 2013 Elsevier Inc. All rights reserved.

Rethinking Extinction

PubMed Central

Dunsmoor, Joseph E.; Niv, Yael; Daw, Nathaniel; Phelps, Elizabeth A.

2015-01-01

Extinction serves as the leading theoretical framework and experimental model to describe how learned behaviors diminish through absence of anticipated reinforcement. In the past decade, extinction has moved beyond the realm of associative learning theory and behavioral experimentation in animals and has become a topic of considerable interest in the neuroscience of learning, memory, and emotion. Here, we review research and theories of extinction, both as a learning process and as a behavioral technique, and consider whether traditional understandings warrant a re-examination. We discuss the neurobiology, cognitive factors, and major computational theories, and revisit the predominant view that extinction results in new learning that interferes with expression of the original memory. Additionally, we reconsider the limitations of extinction as a technique to prevent the relapse of maladaptive behavior, and discuss novel approaches, informed by contemporary theoretical advances, that augment traditional extinction methods to target and potentially alter maladaptive memories. PMID:26447572

The extinction context enables extinction performance after a change in context

PubMed Central

Nelson, James Byron; Gregory, Pamela; Sanjuan, Maria del Carmen

2012-01-01

One experiment with human participants determined the extent to which recovery of extinguished responding with a context switch was due to a failure to retrieve contextually-controlled learning, or some other process such as participants learning that context changes signal reversals in the meaning of stimulus – outcome relationships. In a video game, participants learned to suppress mouse clicking in the presence of a stimulus that predicted an attack. Then, that stimulus underwent extinction in a different context (environment within the game). Following extinction, suppression was recovered and then extinguished again during testing in the conditioning context. In a final test, participants that were tested in the context where extinction first took place showed less of a recovery than those tested in a neutral context, but they showed a recovery of suppression nevertheless. A change in context tended to cause a change in the meaning of the stimulus, leading to recovery in both the neutral and extinction contexts. The extinction context attenuated that recovery, perhaps by enabling retrieval of the learning that took place in extinction. Recovery outside an extinction context is due to a failure of the context to enable the learning acquired during extinction, but only in part. PMID:22521549

Extinction of Learned Fear Induces Hippocampal Place Cell Remapping

PubMed Central

Wang, Melissa E.; Yuan, Robin K.; Keinath, Alexander T.; Ramos Álvarez, Manuel M.

2015-01-01

The extinction of learned fear is a hippocampus-dependent process thought to embody new learning rather than erasure of the original fear memory, although it is unknown how these competing contextual memories are represented in the hippocampus. We previously demonstrated that contextual fear conditioning results in hippocampal place cell remapping and long-term stabilization of novel representations. Here we report that extinction learning also induces place cell remapping in C57BL/6 mice. Specifically, we observed cells that preferentially remapped during different stages of learning. While some cells remapped in both fear conditioning and extinction, others responded predominantly during extinction, which may serve to modify previous representations as well as encode new safe associations. Additionally, we found cells that remapped primarily during fear conditioning, which could facilitate reacquisition of the original fear association. Moreover, we also observed cells that were stable throughout learning, which may serve to encode the static aspects of the environment. The short-term remapping observed during extinction was not found in animals that did not undergo fear conditioning, or when extinction was conducted outside of the conditioning context. Finally, conditioning and extinction produced an increase in spike phase locking to the theta and gamma frequencies. However, the degree of remapping seen during conditioning and extinction only correlated with gamma synchronization. Our results suggest that the extinction learning is a complex process that involves both modification of pre-existing memories and formation of new ones, and these traces coexist within the same hippocampal representation. PMID:26085635

IMPAIRED FEAR EXTINCTION ASSOCIATED WITH PTSD INCREASES WITH HOURS-SINCE-WAKING.

PubMed

Zuj, Daniel V; Palmer, Matthew A; Hsu, Chia-Ming K; Nicholson, Emma L; Cushing, Pippa J; Gray, Kate E; Felmingham, Kim L

2016-03-01

Prior research has demonstrated that time-of-day may play an important role in the extinction of conditioned fear, with extinction better learned earlier in the day rather than later. Impaired fear extinction memory is widely considered a key mechanism of posttraumatic stress disorder (PTSD). The relationship between fear extinction and PTSD symptoms may be moderated by hours-since-waking. In the present experiment, we examined whether hours-since-waking would moderate fear extinction learning ability in a clinical PTSD sample (n = 15), compared to trauma-exposed (n = 33) and nonexposed controls (n = 22). Participants completed a standardized differential fear conditioning and extinction paradigm, providing skin conductance response measures to quantify conditioned responding. Mixed-model analysis of variance revealed a PTSD-specific impairment in extinction learning ability in the late extinction phase. A moderation analysis showed that hours-since-waking was a significant moderator of the relationship between impaired late extinction and PTSD symptoms. Specifically, we found that participants with higher PTSD symptoms demonstrated poorer fear extinction learning ability as they were awake for longer. The results of the current study add to a growing literature indicating deficits in fear extinction learning in PTSD samples, compared to trauma-exposed and nonexposed controls. These results support previous findings that fear extinction is impaired later in the day, and extends this to a clinical sample, suggesting that exposure-therapy may be optimized by scheduling sessions in the morning. © 2016 Wiley Periodicals, Inc.

Effects of D-cycloserine on the extinction of appetitive operant learning.

PubMed

Vurbic, Drina; Gold, Benjamin; Bouton, Mark E

2011-08-01

Four experiments with rat subjects examined whether D-cycloserine (DCS), a partial NMDA agonist, facilitates the extinction of operant lever-pressing reinforced by food. Previous research has demonstrated that DCS facilitates extinction learning with methods that involve Pavlovian extinction. In the current experiments, operant conditioning occurred in Context A, extinction in Context B, and then testing occurred in both the extinction and conditioning contexts. Experiments 1A and 1B tested the effects of three doses of DCS (5, 15, and 30 mg/kg) on the extinction of lever pressing trained as a free operant. Experiment 2 examined their effects when extinction of the free operant was conducted in the presence of nonresponse-contingent deliveries of the reinforcer (that theoretically reduced the role of generalization decrement in suppressing responding). Experiment 3 examined their effects on extinction of a discriminated operant, that is, one that had been reinforced in the presence of a discriminative stimulus, but not in its absence. A strong ABA renewal effect was observed in all four experiments during testing. However, despite the use of DCS doses and a drug administration procedure that facilitates the extinction of Pavlovian learning, there was no evidence in any experiment that DCS facilitated operant extinction learning assessed in either the extinction or the conditioning context. DCS may primarily facilitate learning processes that underlie Pavlovian, rather than purely operant, extinction. (PsycINFO Database Record (c) 2011 APA, all rights reserved).

Inhibiting DNA methylation alters olfactory extinction but not acquisition learning in Apis cerana and Apis mellifera.

PubMed

Gong, Zhiwen; Wang, Chao; Nieh, James C; Tan, Ken

2016-07-01

DNA methylation plays a key role in invertebrate acquisition and extinction memory. Honey bees have excellent olfactory learning, but the role of DNA methylation in memory formation has, to date, only been studied in Apis mellifera. We inhibited DNA methylation by inhibiting DNA methyltransferase (DNMT) with zebularine (zeb) and studied the resulting effects upon olfactory acquisition and extinction memory in two honey bee species, Apis cerana and A. mellifera. We used the proboscis extension reflex (PER) assay to measure memory. We provide the first demonstration that DNA methylation is also important in the olfactory extinction learning of A. cerana. DNMT did not reduce acquisition learning in either species. However, zeb bidirectionally and differentially altered extinction learning in both species. In particular, zeb provided 1h before acquisition learning improved extinction memory retention in A. mellifera, but reduced extinction memory retention in A. cerana. The reasons for these differences are unclear, but provide a basis for future studies to explore species-specific differences in the effects of methylation on memory formation. Copyright © 2016 Elsevier Ltd. All rights reserved.

The Effect of D-Cycloserine on Immediate vs. Delayed Extinction of Learned Fear

ERIC Educational Resources Information Center

Langton, Julia M.; Richardson, Rick

2010-01-01

We compared the effect of D-cycloserine (DCS) on immediate (10 min after conditioning) and delayed (24 h after conditioning) extinction of learned fear in rats. DCS facilitated both immediate and delayed extinction when the drug was administered after extinction training. However, DCS did not facilitate immediate extinction when administered prior…

NMDA receptors in the avian amygdala and the premotor arcopallium mediate distinct aspects of appetitive extinction learning.

PubMed

Gao, Meng; Lengersdorf, Daniel; Stüttgen, Maik C; Güntürkün, Onur

2018-05-02

Extinction learning is an essential mechanism that enables constant adaptation to ever-changing environmental conditions. The underlying neural circuit is mostly studied with rodent models using auditory cued fear conditioning. In order to uncover the variant and the invariant neural properties of extinction learning, we adopted pigeons as an animal model in an appetitive sign-tracking paradigm. The animals firstly learned to respond to two conditioned stimuli in two different contexts (CS-1 in context A and CS-2 in context B), before conditioned responses to the stimuli were extinguished in the opposite contexts (CS-1 in context B and CS-2 in context A). Subsequently, responding to both stimuli was tested in both contexts. Prior to extinction training, we locally injected the N-methyl-d-aspartate receptor (NMDAR) antagonist 2-Amino-5-phosphonovaleric acid (APV) in either the amygdala or the (pre)motor arcopallium to investigate their involvement in extinction learning. Our findings suggest that the encoding of extinction memory required the activation of amygdala, as visible by an impairment of extinction acquisition by concurrent inactivation of local NMDARs. In contrast, consolidation and subsequent retrieval of extinction memory recruited the (pre)motor arcopallium. Also, the inactivation of arcopallial NMDARs induced a general motoric slowing during extinction training. Thus, our results reveal a double dissociation between arcopallium and amygdala with respect to acquisition and consolidation of extinction, respectively. Our study therefore provides new insights on the two key components of the avian extinction network and their resemblance to the data obtained from mammals, possibly indicating a shared neural mechanism underlying extinction learning shaped by evolution. Copyright © 2018 Elsevier B.V. All rights reserved.

Pre-trauma individual differences in extinction learning predict posttraumatic stress.

PubMed

Lommen, Miriam J J; Engelhard, Iris M; Sijbrandij, Marit; van den Hout, Marcel A; Hermans, Dirk

2013-02-01

In the aftermath of a traumatic event, many people suffer from psychological distress, but only a minority develops posttraumatic stress disorder (PTSD). Pre-trauma individual differences in fear conditioning, most notably reduced extinction learning, have been proposed as playing an important role in the etiology of PTSD. However, prospective data are lacking. In this study, we prospectively tested whether reduced extinction was a predictor for later posttraumatic stress. Dutch soldiers (N = 249) were administered a conditioning task before their four-month deployment to Afghanistan to asses individual differences in extinction learning. After returning home, posttraumatic stress was measured. Results showed that reduced extinction learning before deployment predicted subsequent PTSD symptom severity, over and beyond degree of pre-deployment stress symptoms, neuroticism, and exposure to stressors on deployment. The findings suggest that reduced extinction learning may play a role in the development of PTSD. Copyright © 2012 Elsevier Ltd. All rights reserved.

Extinction of Conditioned Fear is Better Learned and Recalled in the Morning than in the Evening

PubMed Central

Pace-Schott, Edward F.; Spencer, Rebecca M.C.; Vijayakumar, Shilpa; Ahmed, Nafis; Verga, Patrick W.; Orr, Scott P.; Pitman, Roger K.; Milad, Mohammed R.

2013-01-01

Sleep helps emotional memories consolidate and may promote generalization of fear extinction memory. We examined whether extinction learning and memory might differ in the morning and evening due, potentially, to circadian and/or sleep-homeostatic factors. Healthy men (N=109) in 6 groups completed a 2-session protocol. In Session 1, fear conditioning was followed by extinction learning. Partial reinforcement with mild electric shock produced conditioned skin conductance responses (SCR) to 2 differently colored lamps (CS+), but not a third color (CS−), within the computer image of a room (conditioning context). One CS+ (CS+E) but not the other (CS+U) was immediately extinguished by un-reinforced presentations in a different room (extinction context). Delay durations of 3 hr (within AM or PM), 12 hr (morning-to-evening or evening-to-morning) or 24 hr (morning-to-morning or evening-to-evening) followed. In Session 2, extinction recall and contextual fear renewal were tested. We observed no significant effects of the delay interval on extinction memory but did observe an effect of time-of-day. Fear extinction was significantly better if learned in the morning (p=.002). Collapsing across CS+ type, there was smaller morning differential SCR at both extinction recall (p=.003) and fear renewal (p=.005). Morning extinction recall showed better generalization from the CS+E to CS+U with the response to the CS+U significantly larger than to the CS+E only in the evening (p=.028). Thus, extinction is learned faster and its memory is better generalized in the morning. Cortisol and testosterone showed the expected greater salivary levels in the morning when higher testosterone/cortisol ratio also predicting better extinction learning. Circadian factors may promote morning extinction. Alternatively, evening homeostatic sleep pressure may impede extinction and favor recall of conditioned fear. PMID:23992769

Extinction of conditioned fear is better learned and recalled in the morning than in the evening.

PubMed

Pace-Schott, Edward F; Spencer, Rebecca M C; Vijayakumar, Shilpa; Ahmed, Nafis A K; Verga, Patrick W; Orr, Scott P; Pitman, Roger K; Milad, Mohammed R

2013-11-01

Sleep helps emotional memories consolidate and may promote generalization of fear extinction memory. We examined whether extinction learning and memory might differ in the morning and evening due, potentially, to circadian and/or sleep-homeostatic factors. Healthy men (N = 109) in 6 groups completed a 2-session protocol. In Session 1, fear conditioning was followed by extinction learning. Partial reinforcement with mild electric shock produced conditioned skin conductance responses (SCRs) to 2 differently colored lamps (CS+), but not a third color (CS-), within the computer image of a room (conditioning context). One CS+ (CS + E) but not the other (CS + U) was immediately extinguished by un-reinforced presentations in a different room (extinction context). Delay durations of 3 h (within AM or PM), 12 h (morning-to-evening or evening-to-morning) or 24 h (morning-to-morning or evening-to-evening) followed. In Session 2, extinction recall and contextual fear renewal were tested. We observed no significant effects of the delay interval on extinction memory but did observe an effect of time-of-day. Fear extinction was significantly better if learned in the morning (p = .002). Collapsing across CS + type, there was smaller morning differential SCR at both extinction recall (p = .003) and fear renewal (p = .005). Morning extinction recall showed better generalization from the CS + E to CS + U with the response to the CS + U significantly larger than to the CS + E only in the evening (p = .028). Thus, extinction is learned faster and its memory is better generalized in the morning. Cortisol and testosterone showed the expected greater salivary levels in the morning when higher testosterone/cortisol ratio also predicted better extinction learning. Circadian factors may promote morning extinction. Alternatively, evening homeostatic sleep pressure may impede extinction and favor recall of conditioned fear. Copyright © 2013 Elsevier Ltd. All rights reserved.

Effects of chemogenetic excitation or inhibition of the ventrolateral periaqueductal gray on the acquisition and extinction of Pavlovian fear conditioning.

PubMed

Arico, Carolyn; Bagley, Elena E; Carrive, Pascal; Assareh, Neda; McNally, Gavan P

2017-10-01

The midbrain periaqueductal gray (PAG) has been implicated in the generation and transmission of a prediction error signal that instructs amygdala-based fear and extinction learning. However, the PAG also plays a key role in the expression of conditioned fear responses. The evidence for a role of the PAG in fear learning and extinction learning has been obtained almost exclusively using PAG-dependent fear responses. It is less clear whether the PAG regulates fear learning when other measures of learned fear are used. Here we combined a chemogenetic approach, permitting excitation or inhibition of neurons in the ventrolateral PAG (VLPAG), with conditioned suppression as the measure of learned fear to assess the role of VLPAG in the acquisition and extinction of fear learning. We show that chemogenetic excitation of VLPAG (with some encroachment on lateral PAG [LPAG]) impairs acquisition of fear and, conversely, chemogenetic inhibition impairs extinction of fear. These effects on fear and extinction learning were specific to the combination of DREADD expression and injection of CNO because they were observed relative to both eYFP controls injected with CNO as well as DREADD expressing controls injected with vehicle. Taken together, these results show that activity of L/VLPAG neurons regulates both the acquisition and extinction of Pavlovian fear learning. Copyright © 2017 Elsevier Inc. All rights reserved.

Extinction of Cocaine Seeking Requires a Window of Infralimbic Pyramidal Neuron Activity after Unreinforced Lever Presses

PubMed Central

Nett, Kelle E.; Cosme, Caitlin V.; Worth, Wensday R.; Wemmie, John A.

2017-01-01

The infralimbic cortex (IL) mediates extinction learning and the active suppression of cocaine-seeking behavior. However, the precise temporal relationship among IL activity, lever pressing, and extinction learning is unclear. To address this issue, we used activity-guided optogenetics in male Sprague Dawley rats to silence IL pyramidal neurons optically for 20 s immediately after unreinforced lever presses during early extinction training after cocaine self-administration. Optical inhibition of the IL increased active lever pressing during shortened extinction sessions, but did not alter the retention of the extinction learning as assessed in ensuing extinction sessions with no optical inhibition. During subsequent cued reinstatement sessions, rats that had previously received optical inhibition during the extinction sessions showed increased cocaine-seeking behavior. These findings appeared to be specific to inhibition during the post-lever press period because IL inhibition given in a noncontingent, pseudorandom manner during extinction sessions did not produce the same effects. Illumination alone (i.e., with no opsin expression) and food-seeking control experiments also failed to produce the same effects. In another experiment, IL inhibition after lever presses during cued reinstatement sessions increased cocaine seeking during those sessions. Finally, inhibition of the prelimbic cortex immediately after unreinforced lever presses during shortened extinction sessions decreased lever pressing during these sessions, but had no effect on subsequent reinstatement. These results indicate that IL activity immediately after unreinforced lever presses is necessary for normal extinction of cocaine seeking, suggesting that critical encoding of the new contingencies between a lever press and a cocaine reward occurs during that period. SIGNIFICANCE STATEMENT The infralimbic cortex (IL) contributes to the extinction of cocaine-seeking behavior, but the precise relationship among IL activity, lever pressing during extinction, and extinction learning has not been elucidated using traditional methods. Using a closed-loop optogenetic approach, we found that selective inhibition of the IL immediately after unreinforced lever pressing impaired within-session extinction learning and promoted the subsequent cued reinstatement of cocaine seeking. These studies suggest that IL activity immediately after the instrumental response during extinction learning of cocaine seeking encodes information required for such learning and that altering such activity produces long-lasting changes in subsequent measures of cocaine craving/relapse. PMID:28539416

Extinction of Cocaine Seeking Requires a Window of Infralimbic Pyramidal Neuron Activity after Unreinforced Lever Presses.

PubMed

Gutman, Andrea L; Nett, Kelle E; Cosme, Caitlin V; Worth, Wensday R; Gupta, Subhash C; Wemmie, John A; LaLumiere, Ryan T

2017-06-21

The infralimbic cortex (IL) mediates extinction learning and the active suppression of cocaine-seeking behavior. However, the precise temporal relationship among IL activity, lever pressing, and extinction learning is unclear. To address this issue, we used activity-guided optogenetics in male Sprague Dawley rats to silence IL pyramidal neurons optically for 20 s immediately after unreinforced lever presses during early extinction training after cocaine self-administration. Optical inhibition of the IL increased active lever pressing during shortened extinction sessions, but did not alter the retention of the extinction learning as assessed in ensuing extinction sessions with no optical inhibition. During subsequent cued reinstatement sessions, rats that had previously received optical inhibition during the extinction sessions showed increased cocaine-seeking behavior. These findings appeared to be specific to inhibition during the post-lever press period because IL inhibition given in a noncontingent, pseudorandom manner during extinction sessions did not produce the same effects. Illumination alone (i.e., with no opsin expression) and food-seeking control experiments also failed to produce the same effects. In another experiment, IL inhibition after lever presses during cued reinstatement sessions increased cocaine seeking during those sessions. Finally, inhibition of the prelimbic cortex immediately after unreinforced lever presses during shortened extinction sessions decreased lever pressing during these sessions, but had no effect on subsequent reinstatement. These results indicate that IL activity immediately after unreinforced lever presses is necessary for normal extinction of cocaine seeking, suggesting that critical encoding of the new contingencies between a lever press and a cocaine reward occurs during that period. SIGNIFICANCE STATEMENT The infralimbic cortex (IL) contributes to the extinction of cocaine-seeking behavior, but the precise relationship among IL activity, lever pressing during extinction, and extinction learning has not been elucidated using traditional methods. Using a closed-loop optogenetic approach, we found that selective inhibition of the IL immediately after unreinforced lever pressing impaired within-session extinction learning and promoted the subsequent cued reinstatement of cocaine seeking. These studies suggest that IL activity immediately after the instrumental response during extinction learning of cocaine seeking encodes information required for such learning and that altering such activity produces long-lasting changes in subsequent measures of cocaine craving/relapse. Copyright © 2017 the authors 0270-6474/17/376075-12$15.00/0.

Recovery effects after extinction in the Morris swimming pool navigation task.

PubMed

Prados, José; Manteiga, Raúl D; Sansa, Joan

2003-08-01

In three experiments in which rats were used as subjects, we developed an extinction procedure using a Morris pool. The animals were trained to find a hidden platform located at a fixed position and were then given extinction trials in which the platform was removed from the pool. When training and extinction were carried out in the same context and time was allowed to elapse between extinction and test, spontaneous recovery of learning was observed. On the other hand, those rats that received extinction in a context different from the one used for training failed to show spontaneous recovery of learning when tested in the extinction context after an interval of 96 h. However, they did show renewal of spatial learning when tested in the training context. These results show that extinction in the spatial domain behaves like extinction in standard conditioning preparations.

Preventing the return of fear using reconsolidation updating and methylene blue is differentially dependent on extinction learning

PubMed Central

Auchter, Allison M.; Shumake, Jason; Gonzalez-Lima, Francisco; Monfils, Marie H.

2017-01-01

Many factors account for how well individuals extinguish conditioned fears, such as genetic variability, learning capacity and conditions under which extinction training is administered. We predicted that memory-based interventions would be more effective to reduce the reinstatement of fear in subjects genetically predisposed to display more extinction learning. We tested this hypothesis in rats genetically selected for differences in fear extinction using two strategies: (1) attenuation of fear memory using post-retrieval extinction training, and (2) pharmacological enhancement of the extinction memory after extinction training by low-dose USP methylene blue (MB). Subjects selectively bred for divergent extinction phenotypes were fear conditioned to a tone stimulus and administered either standard extinction training or retrieval + extinction. Following extinction, subjects received injections of saline or MB. Both reconsolidation updating and MB administration showed beneficial effects in preventing fear reinstatement, but differed in the groups they targeted. Reconsolidation updating showed an overall effect in reducing fear reinstatement, whereas pharmacological memory enhancement using MB was an effective strategy, but only for individuals who were responsive to extinction. PMID:28397861

A Role of Protein Degradation in Memory Consolidation after Initial Learning and Extinction Learning in the Honeybee ("Apis mellifera")

ERIC Educational Resources Information Center

Felsenberg, Johannes; Dombrowski, Vincent; Eisenhardt, Dorothea

2012-01-01

Protein degradation is known to affect memory formation after extinction learning. We demonstrate here that an inhibitor of protein degradation, MG132, interferes with memory formation after extinction learning in a classical appetitive conditioning paradigm. In addition, we find an enhancement of memory formation when the same inhibitor is…

Orbitofrontal cortex inactivation impairs between- but not within-session Pavlovian extinction: an associative analysis.

PubMed

Panayi, Marios C; Killcross, Simon

2014-02-01

The orbitofrontal cortex (OFC) is argued to be the neural locus of Pavlovian outcome expectancies. Reinforcement learning theories argue that extinction learning in Pavlovian procedures is caused by the discrepancy between the expected value of the outcome (US) that is elicited by a predictive stimulus (CS), and the lack of experienced US. If the OFC represents Pavlovian outcome expectancies that are necessary for extinction learning, then disrupting OFC function prior to extinction training should impair extinction learning. This was tested. In experiment 1, Long Evans rats received infusions of saline or muscimol targeting the lateral OFC prior to three appetitive Pavlovian extinction sessions. Muscimol infused into the OFC disrupted between-session but not within-session extinction behaviour. This finding was not due to muscimol infusions disrupting the memory consolidation process per se as there was no effect of muscimol infusion when administered immediately post session (experiment 2). These findings support a role for the OFC in representing outcome expectancies that are necessary for learning. A number of ways in which disrupting outcome expectancy information might block learning will be discussed in the context of traditional associative learning theories and the associative structures they depend on. Copyright © 2013 Elsevier Inc. All rights reserved.

Changes in expression of c-Fos protein following cocaine-cue extinction learning.

PubMed

Nic Dhonnchadha, B Á; Lovascio, B F; Shrestha, N; Lin, A; Leite-Morris, K A; Man, H Y; Kaplan, G B; Kantak, K M

2012-09-01

Extinguishing abnormally strengthened learned responses to cues associated with drugs of abuse remains a key tactic for alleviating addiction. To assist in developing pharmacotherapies to augment exposure therapy for relapse prevention, investigation into neurobiological underpinnings of drug-cue extinction learning is needed. We used regional analyses of c-Fos and GluR2 protein expression to delineate neural activity and plasticity that may be associated with cocaine-cue extinction learning. Rats were trained to self-administer cocaine paired with a light cue, and later underwent a single 2h extinction session for which cocaine was withheld but response-contingent cues were presented (cocaine-cue extinction). Control groups consisted of rats yoked to animals self-administering cocaine and receiving saline non-contingently followed by an extinction session, or rats trained to self-administer cocaine followed by a no-extinction session for which levers were retracted, and cocaine and cues were withheld. Among 11 brain sites examined, extinction training increased c-Fos expression in basolateral amygdala and prelimbic prefrontal cortex of cocaine-cue extinguished rats relative to both control conditions. In dorsal subiculum and infralimbic prefrontal cortex, extinction training increased c-Fos expression in both cocaine-cue and saline-cue extinguished rats relative to the no-extinction control condition. GluR2 protein expression was not altered in any site examined after extinction or control training. Findings suggest that basolateral amygdala and prelimbic prefrontal cortex neurons are activated during acquisition of cocaine-cue extinction learning, a process that is independent of changes in GluR2 abundance. Other sites are implicated in processing the significance of cues that are present early in extinction training. Copyright © 2012 Elsevier B.V. All rights reserved.

Estradiol shifts interactions between the infralimbic cortex and central amygdala to enhance fear extinction memory in female rats.

PubMed

Maeng, Lisa Y; Cover, Kara K; Taha, Mohamad B; Landau, Aaron J; Milad, Mohammed R; Lebrón-Milad, Kelimer

2017-01-02

There is growing evidence that estradiol (E2) enhances fear extinction memory consolidation. However, it is unclear how E2 influences the nodes of the fear extinction network to enhance extinction memory. This study begins to delineate the neural circuits underlying the influence of E2 on fear extinction acquisition and consolidation in female rats. After fear conditioning (day 1), naturally cycling female rats underwent extinction learning (day 2) in a low-E2 state, receiving a systemic administration of either E2 or vehicle prior to extinction training. Extinction memory recall was then tested 24 hr later (day 3). We measured immediate early gene c-fos expression within the extinction network during fear extinction learning and extinction recall. During extinction learning, E2 treatment increased centrolateral amygdala c-fos activity and reduced lateral amygdala activity relative to vehicle. During extinction recall, E2-treated rats exhibited reduced c-fos expression in the centromedial amygdala. There were no group differences in c-fos expression within the medial prefrontal cortex or dorsal hippocampus. Examining c-fos ratios with the infralimbic cortex (IL) revealed that, despite the lack of group differences within the IL, E2 treatment induced greater IL activity relative to both prelimbic cortex and central amygdala (CeA) activity during extinction memory recall. Only the relationship between IL and CeA activity positively correlated with extinction retention. In conclusion, E2 appears to modify interactions between the IL and the CeA in females, shifting from stronger amygdalar modulation of fear during extinction learning to stronger IL control during extinction recall. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Associative learning versus fear habituation as predictors of long-term extinction retention.

PubMed

Brown, Lily A; LeBeau, Richard T; Chat, Ka Yi; Craske, Michelle G

2017-06-01

Violation of unconditioned stimulus (US) expectancy during extinction training may enhance associative learning and result in improved long-term extinction retention compared to within-session habituation. This experiment examines variation in US expectancy (i.e., expectancy violation) as a predictor of long-term extinction retention. It also examines within-session habituation of fear-potentiated startle (electromyography, EMG) and fear of conditioned stimuli (CS) throughout extinction training as predictors of extinction retention. Participants (n = 63) underwent fear conditioning, extinction and retention and provided continuous ratings of US expectancy and EMG, as well as CS fear ratings before and after each phase. Variation in US expectancy throughout extinction and habituation of EMG and fear was entered into a regression as predictors of retention and reinstatement of levels of expectancy and fear. Greater variation in US expectancy throughout extinction training was significantly predictive of enhanced extinction performance measured at retention test, although not after reinstatement test. Slope of EMG and CS fear during extinction did not predict retention of extinction. Within-session habituation of EMG and self-reported fear is not sufficient for long-term retention of extinction learning, and models emphasizing expectation violation may result in enhanced outcomes.

Extinction in multiple contexts: Effects on the rate of extinction and the strength of response recovery.

PubMed

Bustamante, Javier; Uengoer, Metin; Thorwart, Anna; Lachnit, Harald

2016-09-01

In two human predictive-learning experiments, we investigated the effects of extinction in multiple contexts on the rate of extinction and the strength of response recovery. In each experiment, participants initially received acquisition training with a target cue in one context, followed by extinction either in a different context (extinction in a single context) or in three different contexts (extinction in multiple contexts). The results of both experiments showed that conducting extinction in multiple contexts led to higher levels of responding during extinction than did extinction in a single context. Additionally, Experiment 2 showed that extinction in multiple contexts prevented ABC renewal but had no detectable impact on ABA renewal. Our results are discussed within the framework of contemporary learning theories of contextual control and extinction.

Out with the old and in with the new: Synaptic mechanisms of extinction in the amygdala

PubMed Central

Maren, Stephen

2014-01-01

Considerable research indicates that long-term synaptic plasticity in the amygdala underlies the acquisition of emotional memories, including those learned during Pavlovian fear conditioning. Much less is known about the synaptic mechanisms involved in other forms of associative learning, including extinction, that update fear memories. Extinction learning might reverse conditioning-related changes (e.g., depotentiation) or induce plasticity at inhibitory synapses (e.g., long-term potentiation) to suppress conditioned fear responses. Either mechanism must account for fear recovery phenomena after extinction, as well as savings of extinction after fear recovery. PMID:25312830

The Infralimbic Cortex Regulates the Consolidation of Extinction after Cocaine Self-Administration

ERIC Educational Resources Information Center

LaLumiere, Ryan T.; Niehoff, Kate E.; Kalivas, Peter W.

2010-01-01

The infralimbic cortex (IL) regulates the consolidation of extinction learning for fear conditioning. Whether the IL influences the consolidation of extinction learning for cocaine self-administration is unknown. To address this issue, male Sprague-Dawley rats underwent 2 wk of cocaine self-administration followed by extinction training. On the…

Slower Reacquisition after Partial Extinction in Human Contingency Learning

ERIC Educational Resources Information Center

Morís, Joaquín; Barberia, Itxaso; Vadillo, Miguel A.; Andrades, Ainhoa; López, Francisco J.

2017-01-01

Extinction is a very relevant learning phenomenon from a theoretical and applied point of view. One of its most relevant features is that relapse phenomena often take place once the extinction training has been completed. Accordingly, as extinction-based therapies constitute the most widespread empirically validated treatment of anxiety disorders,…

The key role of extinction learning in anxiety disorders: behavioral strategies to enhance exposure-based treatments.

PubMed

Pittig, Andre; van den Berg, Linda; Vervliet, Bram

2016-01-01

Extinction learning is a major mechanism for fear reduction by means of exposure. Current research targets innovative strategies to enhance fear extinction and thereby optimize exposure-based treatments for anxiety disorders. This selective review updates novel behavioral strategies that may provide cutting-edge clinical implications. Recent studies provide further support for two types of enhancement strategies. Procedural enhancement strategies implemented during extinction training translate to how exposure exercises may be conducted to optimize fear extinction. These strategies mostly focus on a maximized violation of dysfunctional threat expectancies and on reducing context and stimulus specificity of extinction learning. Flanking enhancement strategies target periods before and after extinction training and inform optimal preparation and post-processing of exposure exercises. These flanking strategies focus on the enhancement of learning in general, memory (re-)consolidation, and memory retrieval. Behavioral strategies to enhance fear extinction may provide powerful clinical applications to further maximize the efficacy of exposure-based interventions. However, future replications, mechanistic examinations, and translational studies are warranted to verify long-term effects and naturalistic utility. Future directions also comprise the interplay of optimized fear extinction with (avoidance) behavior and motivational antecedents of exposure.

The Plasticity of Extinction: Contribution of the Prefrontal Cortex in Treating Addiction through Inhibitory Learning

PubMed Central

Gass, J. T.; Chandler, L. J.

2013-01-01

Theories of drug addiction that incorporate various concepts from the fields of learning and memory have led to the idea that classical and operant conditioning principles underlie the compulsiveness of addictive behaviors. Relapse often results from exposure to drug-associated cues, and the ability to extinguish these conditioned behaviors through inhibitory learning could serve as a potential therapeutic approach for those who suffer from addiction. This review will examine the evidence that extinction learning alters neuronal plasticity in specific brain regions and pathways. In particular, subregions of the prefrontal cortex (PFC) and their projections to other brain regions have been shown to differentially modulate drug-seeking and extinction behavior. Additionally, there is a growing body of research demonstrating that manipulation of neuronal plasticity can alter extinction learning. Therefore, the ability to alter plasticity within areas of the PFC through pharmacological manipulation could facilitate the acquisition of extinction and provide a novel intervention to aid in the extinction of drug-related memories. PMID:23750137

Slower reacquisition after partial extinction in human contingency learning.

PubMed

Morís, Joaquín; Barberia, Itxaso; Vadillo, Miguel A; Andrades, Ainhoa; López, Francisco J

2017-01-01

Extinction is a very relevant learning phenomenon from a theoretical and applied point of view. One of its most relevant features is that relapse phenomena often take place once the extinction training has been completed. Accordingly, as extinction-based therapies constitute the most widespread empirically validated treatment of anxiety disorders, one of their most important limitations is this potential relapse. We provide the first demonstration of relapse reduction in human contingency learning using mild aversive stimuli. This effect was found after partial extinction (i.e., reinforced trials were occasionally experienced during extinction, Experiment 1) and progressive extinction treatments (Experiment 3), and it was not only because of differences in uncertainty levels between the partial and a standard extinction group (Experiment 2). The theoretical explanation of these results, the potential uses of this strategy in applied situations, and its current limitations are discussed. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Attentional Control and Fear Extinction in Subclinical Fear: An Exploratory Study

PubMed Central

Forcadell, Eduard; Torrents-Rodas, David; Treen, Devi; Fullana, Miquel A.; Tortella-Feliu, Miquel

2017-01-01

Attentional control (AC) and fear extinction learning are known to be involved in pathological anxiety. In this study we explored whether individual differences in non-emotional AC were associated with individual differences in the magnitude and gradient of fear extinction (learning and recall). In 50 individuals with fear of spiders, we collected measures of non-emotional AC by means of self-report and by assessing the functioning of the major attention networks (executive control, orienting, and alerting). The participants then underwent a paradigm assessing fear extinction learning and extinction recall. The two components of the orienting network functioning (costs and benefits) were significantly associated with fear extinction gradient over and above the effects of trait anxiety. Specifically, participants with enhanced orienting costs (i.e., difficulties in disengaging attention from cues not relevant for the task) showed faster extinction learning, while those with enhanced orienting benefits (i.e., attention facilitated by valid cues) exhibited faster extinction recall as measured by fear-potentiated startle and Unconditioned Stimulus expectancies, respectively. Our findings suggest that, in non-emotional conditions, the orienting component of attention may be predictive of fear extinction. They also show that the use of fear extinction gradients and the exploration of individual differences in non-emotional AC (using performance-based measures of attentional network functioning) can provide a better understanding of individual differences in fear learning. Our findings also may help to understand differences in exposure therapy outcomes. PMID:29018384

Deepened extinction following compound stimulus presentation: Noradrenergic modulation

PubMed Central

Janak, Patricia H.; Corbit, Laura H.

2011-01-01

Behavioral extinction is an active form of new learning involving the prediction of nonreward where reward has previously been present. The expression of extinction learning can be disrupted by the presentation of reward itself or reward-predictive stimuli (reinstatement) as well as the passage of time (spontaneous recovery) or contextual changes (renewal). The following experiments replicated the demonstration that presenting multiple previously rewarded stimuli in compound during extinction enhances extinction learning. To explore the pharmacological basis for this we next examined the effects of pharmacological treatments that either facilitated or blocked noradrenergic activity to test the hypothesis that increased noradrenergic activity at the time of extinction training would improve, whereas blockade of noradrenergic activity would impair the extinction of appetitive stimulus–reward memories. Different groups of rats were trained in a discriminative stimulus paradigm to lever-press for food reward. Once stable responding was achieved, responding was extinguished for 2 d. Prior to a third extinction session, rats received systemic administration of either saline, yohimbine (α2 antagonist), atomoxetine (norepinephrine reuptake inhibitor), or propranolol (β-receptor antagonist). Spontaneous recovery of responding to the stimuli was tested 4 wk later. Our results indicate that increasing noradrenergic activity during extinction augments extinction learning resulting in less recovery of responding at test. These results have important implications for models of relapse to drug seeking and the development of extinction-based therapies. PMID:21224211

Extinction learning in childhood anxiety disorders, obsessive compulsive disorder and posttraumatic stress disorder: implications for treatment

PubMed Central

McGuire, Joseph F.; Orr, Scott P.; Essoe, Joey K.-Y.; McCracken, James T.; Storch, Eric A.; Piacentini, John

2018-01-01

Introduction Threat conditioning and extinction play an important role in anxiety disorders, obsessive compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). Although these conditions commonly affect children, threat conditioning and extinction have been primarily studied in adults. However, differences in phenomenology and neural architecture prohibit the generalization of adult findings to youth. Areas covered A comprehensive literature search using PubMed and PsycInfo was conducted to identify studies that have used differential conditioning tasks to examine threat acquisition and extinction in youth. The information obtained from this review helps to clarify the influence of these processes on the etiology and treatment of youth with OCD, PTSD and other anxiety disorders. Thirty studies of threat conditioning and extinction were identified. Expert Commentary Youth with anxiety disorders, OCD, and PTSD have largely comparable threat acquisition relative to unaffected controls, with some distinctions noted for youth with PTSD or youth who have suffered maltreatment. However, impaired extinction was consistently observed across youth with these disorders and appears to be consistent with deficiencies in inhibitory learning. Incorporating strategies to improve inhibitory learning may improve extinction learning within extinction-based treatments like cognitive behavioral therapy (CBT). Strategies to improve inhibitory learning in CBT are discussed. PMID:27275519

Extinction learning in childhood anxiety disorders, obsessive compulsive disorder and post-traumatic stress disorder: implications for treatment.

PubMed

McGuire, Joseph F; Orr, Scott P; Essoe, Joey K-Y; McCracken, James T; Storch, Eric A; Piacentini, John

2016-10-01

Threat conditioning and extinction play an important role in anxiety disorders, obsessive compulsive disorder (OCD), and post-traumatic stress disorder (PTSD). Although these conditions commonly affect children, threat conditioning and extinction have been primarily studied in adults. However, differences in phenomenology and neural architecture prohibit the generalization of adult findings to youth. A comprehensive literature search using PubMed and PsycInfo was conducted to identify studies that have used differential conditioning tasks to examine threat acquisition and extinction in youth. The information obtained from this review helps to clarify the influence of these processes on the etiology and treatment of youth with OCD, PTSD and other anxiety disorders. Thirty studies of threat conditioning and extinction were identified Expert commentary: Youth with anxiety disorders, OCD, and PTSD have largely comparable threat acquisition relative to unaffected controls, with some distinctions noted for youth with PTSD or youth who have suffered maltreatment. However, impaired extinction was consistently observed across youth with these disorders and appears to be consistent with deficiencies in inhibitory learning. Incorporating strategies to improve inhibitory learning may improve extinction learning within extinction-based treatments like cognitive behavioral therapy (CBT). Strategies to improve inhibitory learning in CBT are discussed.

Using c-Jun to identify fear extinction learning-specific patterns of neural activity that are affected by single prolonged stress.

PubMed

Knox, Dayan; Stanfield, Briana R; Staib, Jennifer M; David, Nina P; DePietro, Thomas; Chamness, Marisa; Schneider, Elizabeth K; Keller, Samantha M; Lawless, Caroline

2018-04-02

Neural circuits via which stress leads to disruptions in fear extinction is often explored in animal stress models. Using the single prolonged stress (SPS) model of post traumatic stress disorder and the immediate early gene (IEG) c-Fos as a measure of neural activity, we previously identified patterns of neural activity through which SPS disrupts extinction retention. However, none of these stress effects were specific to fear or extinction learning and memory. C-Jun is another IEG that is sometimes regulated in a different manner to c-Fos and could be used to identify emotional learning/memory specific patterns of neural activity that are sensitive to SPS. Animals were either fear conditioned (CS-fear) or presented with CSs only (CS-only) then subjected to extinction training and testing. C-Jun was then assayed within neural substrates critical for extinction memory. Inhibited c-Jun levels in the hippocampus (Hipp) and enhanced functional connectivity between the ventromedial prefrontal cortex (vmPFC) and basolateral amygdala (BLA) during extinction training was disrupted by SPS in the CS-fear group only. As a result, these effects were specific to emotional learning/memory. SPS also disrupted inhibited Hipp c-Jun levels, enhanced BLA c-Jun levels, and altered functional connectivity among the vmPFC, BLA, and Hipp during extinction testing in SPS rats in the CS-fear and CS-only groups. As a result, these effects were not specific to emotional learning/memory. Our findings suggest that SPS disrupts neural activity specific to extinction memory, but may also disrupt the retention of fear extinction by mechanisms that do not involve emotional learning/memory. Copyright © 2017 Elsevier B.V. All rights reserved.

Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans

PubMed Central

Rabinak, Christine A.; Angstadt, Mike; Lyons, Maryssa; Mori, Shoko; Milad, Mohammed R.; Liberzon, Israel; Phan, K. Luan

2013-01-01

Pre-extinction administration of ∆9-tetrahydrocannibinol (THC) facilitates recall of extinction in healthy humans, and evidence from animal studies suggest that this likely involves via enhancement of the cannabinoid system within the ventromedial prefrontal cortex (vmPFC) and hippocampus (HIPP), brain structures critical to fear extinction. However, the effect of cannabinoids on the underlying neural circuitry of extinction memory recall in humans has not been demonstrated. We conducted a functional magnetic resonance imaging (fMRI) study using a randomized, double-blind, placebo-controlled, between-subjects design (N=14/group) coupled with a standard Pavlovian fear extinction paradigm and an acute pharmacological challenge with oral dronabinol (synthetic THC) in healthy adult volunteers. We examined the effects of THC on vmPFC and HIPP activation when tested for recall of extinction learning 24 hours after extinction learning. Compared to subjects who received placebo, participants who received THC showed increased vmPFC and HIPP activation to a previously extinguished conditioned stimulus (CS+E) during extinction memory recall. This study provides the first evidence that pre-extinction administration of THC modulates prefrontal-limbic circuits during fear extinction in humans and prompts future investigation to test if cannabinoid agonists can rescue or correct the impaired behavioral and neural function during extinction recall in patients with PTSD. Ultimately, the cannabinoid system may serve as a promising target for innovative intervention strategies (e.g. pharmacological enhancement of exposure-based therapy) in PTSD and other fear learning-related disorders. PMID:24055595

Forming Competing Fear Learning and Extinction Memories in Adolescence Makes Fear Difficult to Inhibit

ERIC Educational Resources Information Center

Baker, Kathryn D.; Richardson, Rick

2015-01-01

Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats (n = 170) were tested for extinction retention after conditioning and extinction at different ages.…

Yohimbine Impairs Extinction of Cocaine-Conditioned Place Preference in an [alpha] [subscript 2]-Adrenergic Receptor Independent Process

ERIC Educational Resources Information Center

Davis, Adeola R.; Shields, Angela D.; Brigman, Jonathan L.; Norcross, Maxine; McElligott, Zoe A.; Holmes, Andrew; Winder, Danny G.

2008-01-01

Extinction, a form of learning that has the ability to reshape learned behavior based on new experiences, has been heavily studied utilizing fear learning paradigms. Mechanisms underlying extinction of positive-valence associations, such as drug self-administration and place preference, are poorly understood yet may have important relevance to…

Histone Modifications around Individual BDNF Gene Promoters in Prefrontal Cortex Are Associated with Extinction of Conditioned Fear

ERIC Educational Resources Information Center

Bredy, Timothy W.; Wu, Hao; Crego, Cortney; Zellhoefer, Jessica; Sun, Yi E.; Barad, Mark

2007-01-01

Extinction of conditioned fear is an important model both of inhibitory learning and of behavior therapy for human anxiety disorders. Like other forms of learning, extinction learning is long-lasting and depends on regulated gene expression. Epigenetic mechanisms make an important contribution to persistent changes in gene expression; therefore,…

Cellular and oscillatory substrates of fear extinction learning.

PubMed

Davis, Patrick; Zaki, Yosif; Maguire, Jamie; Reijmers, Leon G

2017-11-01

The mammalian brain contains dedicated circuits for both the learned expression and suppression of fear. These circuits require precise coordination to facilitate the appropriate expression of fear behavior, but the mechanisms underlying this coordination remain unclear. Using a combination of chemogenetics, activity-based neuronal-ensemble labeling and in vivo electrophysiology, we found that fear extinction learning confers on parvalbumin-expressing (PV) interneurons in the basolateral amygdala (BLA) a dedicated role in the selective suppression of a previously encoded fear memory and BLA fear-encoding neurons. In addition, following extinction learning, PV interneurons enable a competing interaction between a 6-12 Hz oscillation and a fear-associated 3-6 Hz oscillation within the BLA. Loss of this competition increases a 3-6 Hz oscillatory signature, with BLA→medial prefrontal cortex directionality signaling the recurrence of fear expression. The discovery of cellular and oscillatory substrates of fear extinction learning that critically depend on BLA PV interneurons could inform therapies aimed at preventing the pathological recurrence of fear following extinction learning.

Cellular and Oscillatory Substrates of Fear Extinction Learning

PubMed Central

Davis, Patrick; Zaki, Yosif; Maguire, Jamie; Reijmers, Leon G.

2018-01-01

The mammalian brain contains dedicated circuits for both the learned expression and suppression of fear. These circuits require precise coordination to facilitate the appropriate expression of fear behavior, but the mechanisms underlying this coordination remain unclear. Using a novel combination of chemogenetics, activity-based neuronal-ensemble labeling, and in vivo electrophysiology, we found that fear extinction learning confers parvalbumin-expressing (PV) interneurons in the basolateral amygdala (BLA) with a dedicated role in the selective suppression of a previously encoded fear memory and BLA fear-encoding neurons. In addition, following extinction learning, PV interneurons enable a competing interaction between a 6–12 Hz oscillation and a fear-associated 3–6 Hz oscillation within the BLA. Loss of this competition increases a 3–6 Hz oscillatory signature, with BLA→mPFC directionality signaling the recurrence of fear expression. The discovery of cellular and oscillatory substrates of fear extinction learning that critically depend on BLA PV-interneurons could inform therapies aimed at preventing the pathological recurrence of fear following extinction learning. PMID:28967909

β-Adrenoceptor Blockade in the Basolateral Amygdala, But Not the Medial Prefrontal Cortex, Rescues the Immediate Extinction Deficit.

PubMed

Giustino, Thomas F; Seemann, Jocelyn R; Acca, Gillian M; Goode, Travis D; Fitzgerald, Paul J; Maren, Stephen

2017-12-01

Early psychological interventions, such as exposure therapy, rely on extinction learning to reduce the development of stress- and trauma-related disorders. However, recent research suggests that extinction often fails to reduce fear when administered soon after trauma. This immediate extinction deficit (IED) may be due to stress-induced dysregulation of neural circuits involved in extinction learning. We have shown that systemic β-adrenoceptor blockade with propranolol rescues the IED, but impairs delayed extinction. Here we sought to determine the neural locus of these effects. Rats underwent auditory fear conditioning and then received either immediate (30 min) or delayed (24 h) extinction training. We used bilateral intracranial infusions of propranolol into either the infralimbic division of the medial prefrontal cortex (mPFC) or the basolateral amygdala (BLA) to examine the effects of β-adrenoceptor blockade on immediate and delayed extinction learning. Interestingly, intra-BLA, but not intra-mPFC, propranolol rescued the IED; animals receiving intra-BLA propranolol prior to immediate extinction showed less spontaneous recovery of fear during extinction retrieval. Importantly, this was not due to impaired consolidation of the conditioning memory. In contrast, neither intra-BLA nor intra-mPFC propranolol affected delayed extinction learning. Overall, these data contribute to a growing literature suggesting dissociable roles for key nodes in the fear extinction circuit depending on the timing of extinction relative to conditioning. These data also suggest that heightened noradrenergic activity in the BLA underlies stress-induced extinction deficits. Propranolol may be a useful adjunct to behavioral therapeutic interventions in recently traumatized individuals who are at risk for developing trauma-related disorders.

The dorsolateral striatum selectively mediates extinction of habit memory.

PubMed

Goodman, Jarid; Ressler, Reed L; Packard, Mark G

2016-12-01

Previous research has indicated a role for the dorsolateral striatum (DLS) in acquisition and retrieval of habit memory. However, the neurobiological mechanisms guiding extinction of habit memory have not been extensively investigated. The present study examined whether the dorsolateral striatum (DLS) is involved in extinction of habit memory in a food-rewarded response learning version of the plus-maze in adult male Long-Evans rats (experiment 1). In addition, to determine whether the role of this brain region in extinction is selective to habit memory, we also examined whether the DLS is required for extinction of hippocampus-dependent spatial memory in a place learning version of the plus-maze (experiment 2). Following acquisition in either task, rats received two days of extinction training, in which the food reward was removed from the maze. The number of perseverative trials (a trial in which the rat made the same previously reinforced body-turn) and latency to reach the previously correct food well were used as measures of extinction. Animals were given immediate post-training intra-DLS administration of the sodium channel blocker bupivacaine or vehicle to determine the effect of DLS inactivation on consolidation of extinction memory in each task. In the response learning task, post-training DLS inactivation impaired consolidation of extinction memory. Injections of bupivacaine delayed 2 h post-training did not affect extinction, indicating a time-dependent effect of neural inactivation on consolidation of extinction memory in this task. In contrast, post-training DLS inactivation did not impair, but instead slightly enhanced, extinction memory in the place learning task. The present findings indicate a critical role for the DLS in extinction of habit memory in the response learning task, and may be relevant to understanding the neural mechanisms through which maladaptive habits in human psychopathologies (e.g. drug addiction) may be suppressed. Copyright © 2016 Elsevier Inc. All rights reserved.

Sleep supports cued fear extinction memory consolidation independent of circadian phase.

PubMed

Melo, Irene; Ehrlich, Ingrid

2016-07-01

Sleep promotes memory, particularly for declarative learning. However, its role in non-declarative, emotional memories is less well understood. Some studies suggest that sleep may influence fear-related memories, and thus may be an important factor determining the outcome of treatments for emotional disorders such as post-traumatic stress disorder. Here, we investigated the effect of sleep deprivation and time of day on fear extinction memory consolidation. Mice were subjected to a cued Pavlovian fear and extinction paradigm at the beginning of their resting or active phase. Immediate post-extinction learning sleep deprivation for 5h compromised extinction memory when tested 24h after learning. Context-dependent extinction memory recall was completely prevented by sleep-manipulation during the resting phase, while impairment was milder during the active phase and extinction memory retained its context-specificity. Importantly, control experiments excluded confounding factors such as differences in baseline locomotion, fear generalization and stress hormone levels. Together, our findings indicate that post-learning sleep supports cued fear extinction memory consolidation in both circadian phases. The lack of correlation between memory efficacy and sleep time suggests that extinction memory may be influenced by specific sleep events in the early consolidation period. Copyright © 2016 Elsevier Inc. All rights reserved.

Differential Regulation of Glutamic Acid Decarboxylase Gene Expression after Extinction of a Recent Memory vs. Intermediate Memory

ERIC Educational Resources Information Center

Sangha, Susan; Ilenseer, Jasmin; Sosulina, Ludmila; Lesting, Jorg; Pape, Hans-Christian

2012-01-01

Extinction reduces fear to stimuli that were once associated with an aversive event by no longer coupling the stimulus with the aversive event. Extinction learning is supported by a network comprising the amygdala, hippocampus, and prefrontal cortex. Previous studies implicate a critical role of GABA in extinction learning, specifically the GAD65…

How partial reinforcement of food cues affects the extinction and reacquisition of appetitive responses. A new model for dieting success?

PubMed

van den Akker, Karolien; Havermans, Remco C; Bouton, Mark E; Jansen, Anita

2014-10-01

Animals and humans can easily learn to associate an initially neutral cue with food intake through classical conditioning, but extinction of learned appetitive responses can be more difficult. Intermittent or partial reinforcement of food cues causes especially persistent behaviour in animals: after exposure to such learning schedules, the decline in responding that occurs during extinction is slow. After extinction, increases in responding with renewed reinforcement of food cues (reacquisition) might be less rapid after acquisition with partial reinforcement. In humans, it may be that the eating behaviour of some individuals resembles partial reinforcement schedules to a greater extent, possibly affecting dieting success by interacting with extinction and reacquisition. Furthermore, impulsivity has been associated with less successful dieting, and this association might be explained by impulsivity affecting the learning and extinction of appetitive responses. In the present two studies, the effects of different reinforcement schedules and impulsivity on the acquisition, extinction, and reacquisition of appetitive responses were investigated in a conditioning paradigm involving food rewards in healthy humans. Overall, the results indicate both partial reinforcement schedules and, possibly, impulsivity to be associated with worse extinction performance. A new model of dieting success is proposed: learning histories and, perhaps, certain personality traits (impulsivity) can interfere with the extinction and reacquisition of appetitive responses to food cues and they may be causally related to unsuccessful dieting. Copyright © 2014 Elsevier Ltd. All rights reserved.

Post-Learning Sleep Transiently Boosts Context Specific Operant Extinction Memory.

PubMed

Borquez, Margarita; Contreras, María P; Vivaldi, Ennio; Born, Jan; Inostroza, Marion

2017-01-01

Operant extinction is learning to supress a previously rewarded behavior. It is known to be strongly associated with the specific context in which it was acquired, which limits the therapeutic use of operant extinction in behavioral treatments, e.g., of addiction. We examined whether sleep influences contextual memory of operant extinction over time, using two different recall tests (Recent and Remote). Rats were trained in an operant conditioning task (lever press) in context A, then underwent extinction training in context B, followed by a 3-h retention period that contained either spontaneous morning sleep, morning sleep deprivation, or spontaneous evening wakefulness. A recall test was performed either immediately after the 3-h experimental retention period (Recent recall) or after 48 h (Remote), in the extinction context B and in a novel context C. The two main findings were: (i) at the Recent recall test, sleep in comparison with sleep deprivation and spontaneous wakefulness enhanced extinction memory but, only in the extinction context B; (ii) at the Remote recall, extinction performance after sleep was enhanced in both contexts B and C to an extent comparable to levels at Recent recall in context B. Interestingly, extinction performance at Remote recall was also improved in the sleep deprivation groups in both contexts, with no difference to performance in the sleep group. Our results suggest that 3 h of post-learning sleep transiently facilitate the context specificity of operant extinction at a Recent recall. However, the improvement and contextual generalization of operant extinction memory observed in the long-term, i.e., after 48 h, does not require immediate post-learning sleep.

Further evidence of auditory extinction in aphasia.

PubMed

Marshall, Rebecca Shisler; Basilakos, Alexandra; Love-Myers, Kim

2013-02-01

Preliminary research (Shisler, 2005) suggests that auditory extinction in individuals with aphasia (IWA) may be connected to binding and attention. In this study, the authors expanded on previous findings on auditory extinction to determine the source of extinction deficits in IWA. Seventeen IWA (M(age) = 53.19 years) and 17 neurologically intact controls (M(age) = 55.18 years) participated. Auditory stimuli were spoken letters presented in a free-field listening environment. Stimuli were presented in single-stimulus stimulation (SSS) or double-simultaneous stimulation (DSS) trials across 5 conditions designed to determine whether extinction is related to binding, inefficient attention resource allocation, or overall deficits in attention. All participants completed all experimental conditions. Significant extinction was demonstrated only by IWA when sounds were different, providing further evidence of auditory extinction. However, binding requirements did not appear to influence the IWA's performance. Results indicate that, for IWA, auditory extinction may not be attributed to a binding deficit or inefficient attention resource allocation because of equivalent performance across all 5 conditions. Rather, overall attentional resources may be influential. Future research in aphasia should explore the effect of the stimulus presentation in addition to the continued study of attention treatment.

Is an epigenetic switch the key to persistent extinction?

PubMed Central

Stafford, James M.; Lattal, K. Matthew

2011-01-01

Many studies of learning have demonstrated that conditioned behavior can be eliminated when previously established relations between stimuli are severed. This extinction process has been extremely important for the development of learning theories and, more recently, for delineating the neurobiological mechanisms that underlie memory. A key finding from behavioral studies of extinction is that extinction eliminates behavior without eliminating the original memory; extinguished behavior often returns with time or with a return to the context in which the original learning occurred. This persistence of the original memory after extinction creates a challenge for clinical applications that use extinction as part of a treatment intervention. Consequently, a goal of recent neurobiological research on extinction is to identify potential pharmacological targets that may result in persistent extinction. Drugs that promote epigenetic changes are particularly promising because they can result in a long-term molecular signal that, combined with the appropriate behavioral treatment, can cause persistent changes in behavior induced by extinction. We will review evidence demonstrating extinction enhancements by drugs that target epigenetic mechanisms and will describe some of the challenges that epigenetic approaches face in promoting persistent suppression of memories. PMID:21536141

Stress enhances the consolidation of extinction memory in a predictive learning task

PubMed Central

Hamacher-Dang, Tanja C.; Engler, Harald; Schedlowski, Manfred; Wolf, Oliver T.

2013-01-01

Extinction is not always permanent, as indicated by several types of recovery effects, such as the renewal effect, which may occur after a context change and points towards the importance of contextual cues. Strengthening the retrieval of extinction memory is a crucial aim of extinction-based psychotherapeutic treatments of anxiety disorders to prevent relapse. Stress is known to modulate learning and memory, with mostly enhancing effects on memory consolidation. However, whether such a consolidation-enhancing effect of acute stress can also be found for extinction memory has not yet been examined in humans. In this study, we investigated the effect of stress after extinction learning on the retrieval of extinction memory in a predictive learning renewal paradigm. Participants took the part of being the doctor of a fictitious patient and learned to predict whether certain food stimuli were associated with “stomach trouble” in two different restaurants (contexts). On the first day, critical stimuli were associated with stomach trouble in context A (acquisition phase). On the second day, these associations were extinguished in context B. Directly after extinction, participants were either exposed to a stressor (socially evaluated cold pressor test; n = 22) or a control condition (n = 24). On the third day, we tested retrieval of critical associations in contexts A and B. Participants exposed to stress after extinction exhibited a reduced recovery of responding at test in context B, suggesting that stress may context-dependently enhance the consolidation of extinction memory. Furthermore, the increase in cortisol in response to the stressor was negatively correlated with the recovery of responding in context A. Our findings suggest that in parallel to the known effects of stress on the consolidation of episodic memory, stress also enhances the consolidation of extinction memory, which might be relevant for potential applications in extinction-based psychotherapy. PMID:23986667

Combining D-cycloserine with appetitive extinction learning modulates amygdala activity during recall.

PubMed

Ebrahimi, Claudia; Koch, Stefan P; Friedel, Eva; Crespo, Ilsoray; Fydrich, Thomas; Ströhle, Andreas; Heinz, Andreas; Schlagenhauf, Florian

2017-07-01

Appetitive Pavlovian conditioning plays a crucial role in the pathogenesis of drug addiction and conditioned reward cues can trigger craving and relapse even after long phases of abstinence. Promising preclinical work showed that the NMDA-receptor partial agonist D-cycloserine (DCS) facilitates Pavlovian extinction learning of fear and drug cues. Furthermore, DCS-augmented exposure therapy seems to be beneficial in various anxiety disorders, while the supposed working mechanism of DCS during human appetitive or aversive extinction learning is still not confirmed. To test the hypothesis that DCS administration before extinction training improves extinction learning, healthy adults (n=32) underwent conditioning, extinction, and extinction recall on three successive days in a randomized, double-blind, placebo-controlled fMRI design. Monetary wins and losses served as unconditioned stimuli during conditioning to probe appetitive and aversive learning. An oral dose of 50mg of DCS or placebo was administered 1h before extinction training and DCS effects during extinction recall were evaluated on a behavioral and neuronal level. We found attenuated amygdala activation in the DCS compared to the placebo group during recall of the extinguished appetitive cue, along with evidence for enhanced functional amygdala-vmPFC coupling in the DCS group. While the absence of additional physiological measures of conditioned responses during recall in this study prevent the evaluation of a behavioral DCS effect, our neuronal findings are in accordance with recent theories linking successful extinction recall in humans to modulatory top-down influences from the vmPFC that inhibit amygdala activation. Our results should encourage further translational studies concerning the usefulness of DCS to target maladaptive Pavlovian reward associations. Copyright © 2017 Elsevier Inc. All rights reserved.

Context and Behavioral Processes in Extinction

ERIC Educational Resources Information Center

Bouton, Mark E.

2004-01-01

This article provides a selective review and integration of the behavioral literature on Pavlovian extinction. The first part reviews evidence that extinction does not destroy the original learning, but instead generates new learning that is especially context-dependent. The second part examines insights provided by research on several related…

Contextual Change After Fear Acquisition Affects Conditioned Responding and the Time Course of Extinction Learning-Implications for Renewal Research.

PubMed

Sjouwerman, Rachel; Niehaus, Johanna; Lonsdorf, Tina B

2015-01-01

Context plays a central role in retrieving (fear) memories. Accordingly, context manipulations are inherent to most return of fear (ROF) paradigms (in particular renewal), involving contextual changes after fear extinction. Context changes are, however, also often embedded during earlier stages of ROF experiments such as context changes between fear acquisition and extinction (e.g., in ABC and ABA renewal). Previous studies using these paradigms have however focused exclusively on the context switch after extinction (i.e., renewal). Thus, the possibility of a general effect of context switch on conditioned responding that may not be conditional to preceding extinction learning remains unstudied. Hence, the current study investigated the impact of a context switch between fear acquisition and extinction on immediate conditioned responding and on the time-course of extinction learning by using a multimodal approach. A group that underwent contextual change after fear conditioning (AB; n = 36) was compared with a group without a contextual change from acquisition to extinction (AA; n = 149), while measuring physiological (skin conductance and fear potentiated startle) measures and subjective fear ratings. Contextual change between fear acquisition and extinction had a pronounced effect on both immediate conditioned responding and on the time course of extinction learning in skin conductance responses and subjective fear ratings. This may have important implications for the mechanisms underlying and the interpretation of the renewal effect (i.e., contextual switch after extinction). Consequently, future studies should incorporate designs and statistical tests that disentangle general effects of contextual change from genuine ROF effects.

A cross species study of heterogeneity in fear extinction learning in relation to FKBP5 variation and expression: Implications for the acute treatment of posttraumatic stress disorder.

PubMed

Galatzer-Levy, Isaac R; Andero, Raül; Sawamura, Takehito; Jovanovic, Tanja; Papini, Santiago; Ressler, Kerry J; Norrholm, Seth Davin

2017-04-01

Deficits in fear extinction learning are hypothesized to underlie the development of posttraumatic stress disorder (PTSD). Such deficits may, in part, be due to genetic and epigenetic variation in the stress related gene FKBP5. Conversely, altering FKBP5 epigenetic responses during memory consolidation may rescue extinction deficits making it a target for acute intervention to prevent the development of PTSD. Study 1 (Humans) examines if FKBP5 single nucleotide polymorphisms (SNPs) and PTSD symptom domains (re-experiencing, avoidance/numbing, hyperarousal) are associated with abnormal fear extinction phenotypes identified using latent growth mixture modeling (LGMM). Study 2 (Mice) tests if increasing doses of dexamethasone administered prior to extinction alters Fkbp5 mRNA production in the amygdala after extinction and recall and prevents the development of abnormal extinction phenotypes. In humans, abnormal extinction was associated with the TT homozygous genotype of FKBP5 SNPs RS9470080 and RS1360780, and hyperarousal symptoms. In mice, dexamethasone 300 μg/kg was associated with increased amygdala Fkbp5 mRNA following extinction and robust extinction learning while lower doses were not associated with amygdala Fkbp5 mRNA or differences in extinction learning. Further, mice that extinguished on dexamethasone 300 μg/kg maintained low levels of freezing behavior during recall training while mRNA levels were no longer elevated. Together, findings indicate that FKBP5 confers risk for fear extinction deficits. However, this risk may be ameliorated by increasing fkbp5 mRNA expression in the amygdala during memory consolidation making this mechanism a plausible point of acute intervention to prevent the development of PTSD. Copyright © 2016 Elsevier Ltd. All rights reserved.

Differential Endocannabinoid Regulation of Extinction in Appetitive and Aversive Barnes Maze Tasks

ERIC Educational Resources Information Center

Harloe, John P.; Thorpe, Andrew J.; Lichtman, Aron H.

2008-01-01

CB[subscript 1] receptor-compromised animals show profound deficits in extinguishing learned behavior from aversive conditioning tasks, but display normal extinction learning in appetitive operant tasks. However, it is difficult to discern whether the differential involvement of the endogenous cannabinoid system on extinction results from the…

Deepened Extinction following Compound Stimulus Presentation: Noradrenergic Modulation

ERIC Educational Resources Information Center

Janak, Patricia H.; Corbit, Laura H.

2011-01-01

Behavioral extinction is an active form of new learning involving the prediction of nonreward where reward has previously been present. The expression of extinction learning can be disrupted by the presentation of reward itself or reward-predictive stimuli (reinstatement) as well as the passage of time (spontaneous recovery) or contextual changes…

Cued Reacquisition Trials during Extinction Weaken Contextual Renewal in Human Predictive Learning

ERIC Educational Resources Information Center

Effting, Marieke; Vervliet, Bram; Beckers, Tom; Kindt, Merel

2013-01-01

Extinction is generally more context specific than acquisition, as illustrated by the renewal effect. While most strategies to counteract renewal focus on decreasing the context specificity of extinction, the present work aimed at increasing the context specificity of acquisition learning. Two experiments examined whether presenting cued…

Reminder Cues Modulate the Renewal Effect in Human Predictive Learning

PubMed Central

Bustamante, Javier; Uengoer, Metin; Lachnit, Harald

2016-01-01

Associative learning refers to our ability to learn about regularities in our environment. When a stimulus is repeatedly followed by a specific outcome, we learn to expect the outcome in the presence of the stimulus. We are also able to modify established expectations in the face of disconfirming information (the stimulus is no longer followed by the outcome). Both the change of environmental regularities and the related processes of adaptation are referred to as extinction. However, extinction does not erase the initially acquired expectations. For instance, following successful extinction, the initially learned expectations can recover when there is a context change – a phenomenon called the renewal effect, which is considered as a model for relapse after exposure therapy. Renewal was found to be modulated by reminder cues of acquisition and extinction. However, the mechanisms underlying the effectiveness of reminder cues are not well understood. The aim of the present study was to investigate the impact of reminder cues on renewal in the field of human predictive learning. Experiment I demonstrated that renewal in human predictive learning is modulated by cues related to acquisition or extinction. Initially, participants received pairings of a stimulus and an outcome in one context. These stimulus-outcome pairings were preceded by presentations of a reminder cue (acquisition cue). Then, participants received extinction in a different context in which presentations of the stimulus were no longer followed by the outcome. These extinction trials were preceded by a second reminder cue (extinction cue). During a final phase conducted in a third context, participants showed stronger expectations of the outcome in the presence of the stimulus when testing was accompanied by the acquisition cue compared to the extinction cue. Experiment II tested an explanation of the reminder cue effect in terms of simple cue-outcome associations. Therefore, acquisition and extinction cues were equated for their associative histories in Experiment II, which should abolish their impact on renewal if based on simple cue-outcome associations. In contrast to this prediction, Experiment II replicated the findings from Experiment I indicating that the effectiveness of reminder cues did not require direct reminder cue-outcome associations. PMID:28066293

Cholinergic regulation of fear learning and extinction.

PubMed

Wilson, Marlene A; Fadel, Jim R

2017-03-01

Cholinergic activation regulates cognitive function, particularly long-term memory consolidation. This Review presents an overview of the anatomical, neurochemical, and pharmacological evidence supporting the cholinergic regulation of Pavlovian contextual and cue-conditioned fear learning and extinction. Basal forebrain cholinergic neurons provide inputs to neocortical regions and subcortical limbic structures such as the hippocampus and amygdala. Pharmacological manipulations of muscarinic and nicotinic receptors support the role of cholinergic processes in the amygdala, hippocampus, and prefrontal cortex in modulating the learning and extinction of contexts or cues associated with threat. Additional evidence from lesion studies and analysis of in vivo acetylcholine release with microdialysis similarly support a critical role of cholinergic neurotransmission in corticoamygdalar or corticohippocampal circuits during acquisition of fear extinction. Although a few studies have suggested a complex role of cholinergic neurotransmission in the cellular plasticity essential for extinction learning, more work is required to elucidate the exact cholinergic mechanisms and physiological role of muscarinic and nicotinic receptors in these fear circuits. Such studies are important for elucidating the role of cholinergic neurotransmission in disorders such as posttraumatic stress disorder that involve deficits in extinction learning as well as for developing novel therapeutic approaches for such disorders. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A sphingolipid mechanism for behavioral extinction.

PubMed

Huston, Joseph P; Kornhuber, Johannes; Mühle, Christiane; Japtok, Lukasz; Komorowski, Mara; Mattern, Claudia; Reichel, Martin; Gulbins, Erich; Kleuser, Burkhard; Topic, Bianca; De Souza Silva, Maria A; Müller, Christian P

2016-05-01

Reward-dependent instrumental behavior must continuously be re-adjusted according to environmental conditions. Failure to adapt to changes in reward contingencies may incur psychiatric disorders like anxiety and depression. When an expected reward is omitted, behavior undergoes extinction. While extinction involves active re-learning, it is also accompanied by emotional behaviors indicative of frustration, anxiety, and despair (extinction-induced depression). Here, we report evidence for a sphingolipid mechanism in the extinction of behavior. Rapid extinction, indicating efficient re-learning, coincided with a decrease in the activity of the enzyme acid sphingomyelinase (ASM), which catalyzes turnover of sphingomyelin to ceramide, in the dorsal hippocampus of rats. The stronger the decline in ASM activity, the more rapid was the extinction. Sphingolipid-focused lipidomic analysis showed that this results in a decline of local ceramide species in the dorsal hippocampus. Ceramides shape the fluidity of lipid rafts in synaptic membranes and by that way can control neural plasticity. We also found that aging modifies activity of enzymes and ceramide levels in selective brain regions. Aging also changed how the chronic treatment with corticosterone (stress) or intranasal dopamine modified regional enzyme activity and ceramide levels, coinciding with rate of extinction. These data provide first evidence for a functional ASM-ceramide pathway in the brain involved in the extinction of learned behavior. This finding extends the known cellular mechanisms underlying behavioral plasticity to a new class of membrane-located molecules, the sphingolipids, and their regulatory enzymes, and may offer new treatment targets for extinction- and learning-related psychopathological conditions. Sphingolipids are common lipids in the brain which form lipid domains at pre- and postsynaptic membrane compartments. Here we show a decline in dorsal hippocampus ceramide species together with a reduction of acid sphingomyelinase activity during extinction of conditioned behavior in rats. This reduction was associated with expression of re-learning-related behavior, but not with emotional behaviors. Read the Editorial Highlight for this article on page 485. © 2016 International Society for Neurochemistry.

Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior

PubMed Central

Cannady, Reginald; McGonigal, Justin T.; Newsom, Ryan J.; Woodward, John J.

2017-01-01

Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu5 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (KCa2) channels have also been implicated in extinction learning of fear memories, and mGlu5 receptor activation can reduce KCa2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined KCa2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats. This study also explored related neuronal and synaptic mechanisms within the IL-PFC that underlie mGlu5-dependent enhancement of extinction learning. Using whole-cell patch-clamp electrophysiology, activation of mGlu5 in ex vivo slices significantly reduced KCa2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional downregulation of KCa2 channel activity by mGlu5 receptors. Additionally, positive modulation of KCa2 channels prevented mGlu5 receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (KCa2 channel allosteric inhibitor) significantly enhanced extinction of alcohol-seeking behavior across multiple extinction sessions, an effect that persisted for 3 weeks, but was not observed after apamin microinfusions into the prelimbic PFC. Positive modulation of IL-PFC KCa2 channels significantly attenuated mGlu5-dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu5-dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of KCa2 channels. Moreover, these findings demonstrate that KCa2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior. SIGNIFICANCE STATEMENT Alcohol use disorder is a chronic relapsing disorder that is associated with compulsive alcohol-seeking behavior. One of the main causes of alcohol relapse is the craving caused by environmental cues that are associated with alcohol. These cues are formed by normal learning and memory principles, and the understanding of the brain mechanisms that help form these associations can lead to the development of drugs and/or behavior therapies that reduce the impact that these cues have on relapse in alcoholics. PMID:28320841

Behavioral tagging of extinction learning.

PubMed

de Carvalho Myskiw, Jociane; Benetti, Fernando; Izquierdo, Iván

2013-01-15

Extinction of contextual fear in rats is enhanced by exposure to a novel environment at 1-2 h before or 1 h after extinction training. This effect is antagonized by administration of protein synthesis inhibitors anisomycin and rapamycin into the hippocampus, but not into the amygdala, immediately after either novelty or extinction training, as well as by the gene expression blocker 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole administered after novelty training, but not after extinction training. Thus, this effect can be attributed to a mechanism similar to synaptic tagging, through which long-term potentiation can be enhanced by other long-term potentiations or by exposure to a novel environment in a protein synthesis-dependent fashion. Extinction learning produces a tag at the appropriate synapses, whereas novelty learning causes the synthesis of plasticity-related proteins that are captured by the tag, strengthening the synapses that generated this tag.

The Metabotropic Glutamate Receptor, mGlu5, Is Required for Extinction Learning That Occurs in the Absence of a Context Change

PubMed Central

André, Marion Agnes Emma; Güntürkün, Onur; Manahan-Vaughan, Denise

2015-01-01

The metabotropic glutamate (mGlu) receptors and, in particular, mGlu5 are crucially involved in multiple forms of synaptic plasticity that are believed to underlie explicit memory. MGlu5 is also required for information transfer through neuronal oscillations and for spatial memory. Furthermore, mGlu5 is involved in extinction of implicit forms of learning. This places this receptor in a unique position with regard to information encoding. Here, we explored the role of this receptor in context-dependent extinction learning under constant, or changed, contextual conditions. Animals were trained over 3 days to take a left turn under 25% reward probability in a T-maze with a distinct floor pattern (Context A). On Day 4, they experienced either a floor pattern change (Context B) or the same floor pattern (Context A) in the absence of reward. After acquisition of the task, the animals were returned to the maze once more on Day 5 (Context A, no reward). Treatment with the mGlu5 antagonist, 2-methyl-6-(phenylethynyl) pyridine, before maze exposure on Day 4 completely inhibited extinction learning in the AAA paradigm but had no effect in the ABA paradigm. A subsequent return to the original context (A, on Day 5) revealed successful extinction in the AAA paradigm, but impairment of extinction in the ABA paradigm. These data support that although extinction learning in a new context is unaffected by mGlu5 antagonism, extinction of the consolidated context is impaired. This suggests that mGlu5 is intrinsically involved in enabling learning that once-relevant information is no longer valid. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc. PMID:25160592

The metabotropic glutamate receptor, mGlu5, is required for extinction learning that occurs in the absence of a context change.

PubMed

André, Marion Agnes Emma; Güntürkün, Onur; Manahan-Vaughan, Denise

2015-02-01

The metabotropic glutamate (mGlu) receptors and, in particular, mGlu5 are crucially involved in multiple forms of synaptic plasticity that are believed to underlie explicit memory. MGlu5 is also required for information transfer through neuronal oscillations and for spatial memory. Furthermore, mGlu5 is involved in extinction of implicit forms of learning. This places this receptor in a unique position with regard to information encoding. Here, we explored the role of this receptor in context-dependent extinction learning under constant, or changed, contextual conditions. Animals were trained over 3 days to take a left turn under 25% reward probability in a T-maze with a distinct floor pattern (Context A). On Day 4, they experienced either a floor pattern change (Context B) or the same floor pattern (Context A) in the absence of reward. After acquisition of the task, the animals were returned to the maze once more on Day 5 (Context A, no reward). Treatment with the mGlu5 antagonist, 2-methyl-6-(phenylethynyl) pyridine, before maze exposure on Day 4 completely inhibited extinction learning in the AAA paradigm but had no effect in the ABA paradigm. A subsequent return to the original context (A, on Day 5) revealed successful extinction in the AAA paradigm, but impairment of extinction in the ABA paradigm. These data support that although extinction learning in a new context is unaffected by mGlu5 antagonism, extinction of the consolidated context is impaired. This suggests that mGlu5 is intrinsically involved in enabling learning that once-relevant information is no longer valid. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.

Temporal Dynamics of Recovery from Extinction Shortly after Extinction Acquisition

ERIC Educational Resources Information Center

Archbold, Georgina E.; Dobbek, Nick; Nader, Karim

2013-01-01

Evidence suggests that extinction is new learning. Memory acquisition involves both short-term memory (STM) and long-term memory (LTM) components; however, few studies have examined early phases of extinction retention. Retention of auditory fear extinction was examined at various time points. Shortly (1-4 h) after extinction acquisition…

d-Cycloserine reduces context specificity of sexual extinction learning.

PubMed

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Trimbos, Baptist; Both, Stephanie

2015-11-01

d-Cycloserine (DCS) enhances extinction processes in animals. Although classical conditioning is hypothesized to play a pivotal role in the aetiology of appetitive motivation problems, no research has been conducted on the effect of DCS on the reduction of context specificity of extinction in human appetitive learning, while facilitation hereof is relevant in the context of treatment of problematic reward-seeking behaviors. Female participants were presented with two conditioned stimuli (CSs) that either predicted (CS+) or did not predict (CS-) a potential sexual reward (unconditioned stimulus (US); genital vibrostimulation). Conditioning took place in context A and extinction in context B. Subjects received DCS (125mg) or placebo directly after the experiment on day 1 in a randomized, double-blind, between-subject fashion (Placebo n=31; DCS n=31). Subsequent testing for CS-evoked conditioned responses (CRs) in both the conditioning (A) and the extinction context (B) took place 24h later on day 2. Drug effects on consolidation were then assessed by comparing the recall of sexual extinction memories between the DCS and the placebo groups. Post learning administration of DCS facilitates sexual extinction memory consolidation and affects extinction's fundamental context specificity, evidenced by reduced conditioned genital and subjective sexual responses, relative to placebo, for presentations of the reward predicting cue 24h later outside the extinction context. DCS makes appetitive extinction memories context-independent and prevents the return of conditioned response. NMDA receptor glycine site agonists may be potential pharmacotherapies for the prevention of relapse of appetitive motivation disorders with a learned component. Copyright © 2015 Elsevier Inc. All rights reserved.

Effects of prior cocaine versus morphine or heroin self-administration on extinction learning driven by overexpectation versus omission of reward.

PubMed

Lucantonio, Federica; Kambhampati, Sarita; Haney, Richard Z; Atalayer, Deniz; Rowland, Neil E; Shaham, Yavin; Schoenbaum, Geoffrey

2015-05-15

Addiction is characterized by an inability to stop using drugs, despite adverse consequences. One contributing factor to this compulsive drug taking could be the impact of drug use on the ability to extinguish drug seeking after changes in expected outcomes. Here, we compared effects of cocaine, morphine, and heroin self-administration on two forms of extinction learning: standard extinction driven by reward omission and extinction driven by reward overexpectation. In experiment 1, we trained rats to self-administer cocaine, morphine, or sucrose for 3 hours per day (limited access). In experiment 2, we trained rats to self-administer heroin or sucrose for 12 hours per day (extended access). Three weeks later, we trained the rats to associate several cues with palatable food reward, after which we assessed extinction of the learned Pavlovian response, first by pairing two cues together in the overexpectation procedure and later by omitting the food reward. Rats trained under limited access conditions to self-administer sucrose or morphine demonstrated normal extinction in response to both overexpectation and reward omission, whereas cocaine-experienced rats or rats trained to self-administer heroin under extended access conditions exhibited normal extinction in response to reward omission but failed to show extinction in response to overexpectation. Here we show that cocaine and heroin can induce long-lasting deficits in the ability to extinguish reward seeking. These deficits were not observed in a standard extinction procedure but instead only affected extinction learning driven by a more complex phenomenon of overexpectation. Published by Elsevier Inc.

Noradrenergic stimulation modulates activation of extinction-related brain regions and enhances contextual extinction learning without affecting renewal

PubMed Central

Lissek, Silke; Glaubitz, Benjamin; Güntürkün, Onur; Tegenthoff, Martin

2015-01-01

Renewal in extinction learning describes the recovery of an extinguished response if the extinction context differs from the context present during acquisition and recall. Attention may have a role in contextual modulation of behavior and contribute to the renewal effect, while noradrenaline (NA) is involved in attentional processing. In this functional magnetic resonance imaging (fMRI) study we investigated the role of the noradrenergic system for behavioral and brain activation correlates of contextual extinction and renewal, with a particular focus upon hippocampus and ventromedial prefrontal cortex (PFC), which have crucial roles in processing of renewal. Healthy human volunteers received a single dose of the NA reuptake inhibitor atomoxetine prior to extinction learning. During extinction of previously acquired cue-outcome associations, cues were presented in a novel context (ABA) or in the acquisition context (AAA). In recall, all cues were again presented in the acquisition context. Atomoxetine participants (ATO) showed significantly faster extinction compared to placebo (PLAC). However, atomoxetine did not affect renewal. Hippocampal activation was higher in ATO during extinction and recall, as was ventromedial PFC activation, except for ABA recall. Moreover, ATO showed stronger recruitment of insula, anterior cingulate, and dorsolateral/orbitofrontal PFC. Across groups, cingulate, hippocampus and vmPFC activity during ABA extinction correlated with recall performance, suggesting high relevance of these regions for processing the renewal effect. In summary, the noradrenergic system appears to be involved in the modification of established associations during extinction learning and thus has a role in behavioral flexibility. The assignment of an association to a context and the subsequent decision on an adequate response, however, presumably operate largely independently of noradrenergic mechanisms. PMID:25745389

Enhanced extinction of cocaine seeking in brain-derived neurotrophic factor Val66Met knock-in mice.

PubMed

Briand, Lisa A; Lee, Francis S; Blendy, Julie A; Pierce, R Christopher

2012-03-01

The Val66Met polymorphism in the brain-derived neurotropic factor (BDNF) gene results in alterations in fear extinction behavior in both human populations and mouse models. However, it is not clear whether this polymorphism plays a similar role in extinction of appetitive behaviors. Therefore, we examined operant learning and extinction of both food and cocaine self-administration behavior in an inbred genetic knock-in mouse strain expressing the variant Bdnf. These mice provide a unique opportunity to relate alterations in aversive and appetitive extinction learning as well as provide insight into how human genetic variation can lead to differences in behavior. BDNF(Met/Met) mice exhibited a severe deficit in operant learning as demonstrated by an inability to learn the food self-administration task. Therefore, extinction experiments were performed comparing wildtype (BDNF(Val/Val) ) animals to mice heterozygous for the Met allele (BDNF(Val/Met) ), which did not differ in food or cocaine self-administration behavior. In contrast to the deficit in fear extinction previously demonstrated in these mice, we found that BDNF(Val/Met) mice exhibited more rapid extinction of cocaine responding compared to wildtype mice. No differences were found between the genotypes in the extinction of food self-administration behavior or the reinstatement of cocaine seeking, indicating that the effect is specific to extinction of cocaine responding. These results suggest that the molecular mechanisms underlying aversive and appetitive extinction are distinct from one another and BDNF may play opposing roles in the two phenomena. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Global forest loss disproportionately erodes biodiversity in intact landscapes.

PubMed

Betts, Matthew G; Wolf, Christopher; Ripple, William J; Phalan, Ben; Millers, Kimberley A; Duarte, Adam; Butchart, Stuart H M; Levi, Taal

2017-07-27

Global biodiversity loss is a critical environmental crisis, yet the lack of spatial data on biodiversity threats has hindered conservation strategies. Theory predicts that abrupt biodiversity declines are most likely to occur when habitat availability is reduced to very low levels in the landscape (10-30%). Alternatively, recent evidence indicates that biodiversity is best conserved by minimizing human intrusion into intact and relatively unfragmented landscapes. Here we use recently available forest loss data to test deforestation effects on International Union for Conservation of Nature Red List categories of extinction risk for 19,432 vertebrate species worldwide. As expected, deforestation substantially increased the odds of a species being listed as threatened, undergoing recent upgrading to a higher threat category and exhibiting declining populations. More importantly, we show that these risks were disproportionately high in relatively intact landscapes; even minimal deforestation has had severe consequences for vertebrate biodiversity. We found little support for the alternative hypothesis that forest loss is most detrimental in already fragmented landscapes. Spatial analysis revealed high-risk hot spots in Borneo, the central Amazon and the Congo Basin. In these regions, our model predicts that 121-219 species will become threatened under current rates of forest loss over the next 30 years. Given that only 17.9% of these high-risk areas are formally protected and only 8.9% have strict protection, new large-scale conservation efforts to protect intact forests are necessary to slow deforestation rates and to avert a new wave of global extinctions.

Increased prefrontal cortex neurogranin enhances plasticity and extinction learning.

PubMed

Zhong, Ling; Brown, Joshua; Kramer, Audra; Kaleka, Kanwardeep; Petersen, Amber; Krueger, Jamie N; Florence, Matthew; Muelbl, Matthew J; Battle, Michelle; Murphy, Geoffrey G; Olsen, Christopher M; Gerges, Nashaat Z

2015-05-13

Increasing plasticity in neurons of the prefrontal cortex (PFC) has been proposed as a possible therapeutic tool to enhance extinction, a process that is impaired in post-traumatic stress disorder, schizophrenia, and addiction. To test this hypothesis, we generated transgenic mice that overexpress neurogranin (a calmodulin-binding protein that facilitates long-term potentiation) in the PFC. Neurogranin overexpression in the PFC enhanced long-term potentiation and increased the rates of extinction learning of both fear conditioning and sucrose self-administration. Our results indicate that elevated neurogranin function within the PFC can enhance local plasticity and increase the rate of extinction learning across different behavioral tasks. Thus, neurogranin can provide a molecular link between enhanced plasticity and enhanced extinction. Copyright © 2015 the authors 0270-6474/15/357503-06$15.00/0.

Sensory Cortical Population Dynamics Uniquely Track Behavior across Learning and Extinction

PubMed Central

Katz, Donald B.

2014-01-01

Neural responses in many cortical regions encode information relevant to behavior: information that necessarily changes as that behavior changes with learning. Although such responses are reasonably theorized to be related to behavior causation, the true nature of that relationship cannot be clarified by simple learning studies, which show primarily that responses change with experience. Neural activity that truly tracks behavior (as opposed to simply changing with experience) will not only change with learning but also change back when that learning is extinguished. Here, we directly probed for this pattern, recording the activity of ensembles of gustatory cortical single neurons as rats that normally consumed sucrose avidly were trained first to reject it (i.e., conditioned taste aversion learning) and then to enjoy it again (i.e., extinction), all within 49 h. Both learning and extinction altered cortical responses, consistent with the suggestion (based on indirect evidence) that extinction is a novel form of learning. But despite the fact that, as expected, postextinction single-neuron responses did not resemble “naive responses,” ensemble response dynamics changed with learning and reverted with extinction: both the speed of stimulus processing and the relationships among ensemble responses to the different stimuli tracked behavioral relevance. These data suggest that population coding is linked to behavior with a fidelity that single-neuron coding is not. PMID:24453316

Extinction of Pavlovian conditioning: The influence of trial number and reinforcement history.

PubMed

Chan, C K J; Harris, Justin A

2017-08-01

Pavlovian conditioning is sensitive to the temporal relationship between the conditioned stimulus (CS) and the unconditioned stimulus (US). This has motivated models that describe learning as a process that continuously updates associative strength during the trial or specifically encodes the CS-US interval. These models predict that extinction of responding is also continuous, such that response loss is proportional to the cumulative duration of exposure to the CS without the US. We review evidence showing that this prediction is incorrect, and that extinction is trial-based rather than time-based. We also present two experiments that test the importance of trials versus time on the Partial Reinforcement Extinction Effect (PREE), in which responding extinguishes more slowly for a CS that was inconsistently reinforced with the US than for a consistently reinforced one. We show that increasing the number of extinction trials of the partially reinforced CS, relative to the consistently reinforced CS, overcomes the PREE. However, increasing the duration of extinction trials by the same amount does not overcome the PREE. We conclude that animals learn about the likelihood of the US per trial during conditioning, and learn trial-by-trial about the absence of the US during extinction. Moreover, what they learn about the likelihood of the US during conditioning affects how sensitive they are to the absence of the US during extinction. Copyright © 2017 Elsevier B.V. All rights reserved.

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning

PubMed Central

Young, M B; Andero, R; Ressler, K J; Howell, L L

2015-01-01

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg−1) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1  μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning. PMID:26371762

3,4-Methylenedioxymethamphetamine facilitates fear extinction learning.

PubMed

Young, M B; Andero, R; Ressler, K J; Howell, L L

2015-09-15

Acutely administered 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') has been proposed to have long-term positive effects on post-traumatic stress disorder (PTSD) symptoms when combined with psychotherapy. No preclinical data support a mechanistic basis for these claims. Given the persistent nature of psychotherapeutic gains facilitated by MDMA, we hypothesized that MDMA improves fear extinction learning, a key process in exposure-based therapies for PTSD. In these experiments, mice were first exposed to cued fear conditioning and treated with drug vehicle or MDMA before extinction training 2 days later. MDMA was administered systemically and also directly targeted to brain structures known to contribute to extinction. In addition to behavioral measures of extinction, changes in mRNA levels of brain-derived neurotrophic factor (Bdnf) and Fos were measured after MDMA treatment and extinction. MDMA (7.8 mg kg(-1)) persistently and robustly enhanced long-term extinction when administered before extinction training. MDMA increased the expression of Fos in the amygdala and medial prefrontal cortex (mPFC), whereas increases in Bdnf expression were observed only in the amygdala after extinction training. Extinction enhancements were recapitulated when MDMA (1 μg) was infused directly into the basolateral complex of the amygdala (BLA), and enhancement was abolished when BDNF signaling was inhibited before extinction. These findings suggest that MDMA enhances fear memory extinction through a BDNF-dependent mechanism, and that MDMA may be a useful adjunct to exposure-based therapies for PTSD and other anxiety disorders characterized by altered fear learning.

Context Switch Effects on Acquisition and Extinction in Human Predictive Learning

ERIC Educational Resources Information Center

Rosas, Juan M.; Callejas-Aguilera, Jose E.

2006-01-01

Four experiments tested context switch effects on acquisition and extinction in human predictive learning. A context switch impaired probability judgments about a cue-outcome relationship when the cue was trained in a context in which a different cue underwent extinction. The context switch also impaired judgments about a cue trained in a context…

Blockade of Dopamine Activity in the Nucleus Accumbens Impairs Learning Extinction of Conditioned Fear

ERIC Educational Resources Information Center

Holtzman-Assif, Orit; Laurent, Vincent; Westbrook, R. Frederick

2010-01-01

Three experiments used rats to investigate the role of dopamine activity in learning to inhibit conditioned fear responses (freezing) in extinction. In Experiment 1, rats systemically injected with the D2 dopamine antagonist, haloperidol, froze more across multiple extinction sessions and on a drug-free retention test than control rats. In…

Extinction and Renewal of Pavlovian Modulation in Human Sequential Feature Positive Discrimination Learning

ERIC Educational Resources Information Center

Baeyens, Frank; Vansteenwegen, Debora; Beckers, Tom; Hermans, Dirk; Kerkhof, Ineke; De Ceulaer, Annick

2005-01-01

Using a conditioned suppression task, we investigated extinction and renewal of Pavlovian modulation in human sequential Feature Positive (FP) discrimination learning. In Experiment 1, in context a participants were first trained on two FP discriminations, X[right arrow]A+/A- and Y[right arrow]B+/B-. Extinction treatment was administered in the…

Caloric restriction enhances fear extinction learning in mice.

PubMed

Riddle, Megan C; McKenna, Morgan C; Yoon, Yone J; Pattwell, Siobhan S; Santos, Patricia Mae G; Casey, B J; Glatt, Charles E

2013-05-01

Fear extinction learning, the ability to reassess a learned cue of danger as safe when it no longer predicts aversive events, is often dysregulated in anxiety disorders. Selective serotonin reuptake inhibitors (SSRI's) enhance neural plasticity and their ability to enhance fear extinction learning may explain their anxiolytic properties. Caloric restriction (CR) has SSRI-like effects on neural plasticity and anxiety-related behavior. We implemented CR in mice to determine its effects on conditioned-fear responses. Wild type and serotonin transporter (SERT) knockout mice underwent CR for 7 days leading to significant weight loss. Mice were then tested for cued fear learning and anxiety-related behavior. CR markedly enhanced fear extinction learning and its retention in adolescent female mice, and adults of both sexes. These effects of CR were absent in SERT knockout mice. Moreover, CR phenocopied behavioral and molecular effects of chronic fluoxetine, but there was no additive effect of CR in fluoxetine-treated mice. These results demonstrate that CR enhances fear extinction learning through a SERT-dependent mechanism. These results may have implications for eating disorders such as anorexia nervosa (AN), in which there is a high prevalence of anxiety before the onset of dietary restriction and support proposals that in AN, CR is a motivated effort to control dysregulated fear responses and elevated anxiety.

Working Memory and Reinforcement Schedule Jointly Determine Reinforcement Learning in Children: Potential Implications for Behavioral Parent Training

PubMed Central

Segers, Elien; Beckers, Tom; Geurts, Hilde; Claes, Laurence; Danckaerts, Marina; van der Oord, Saskia

2018-01-01

Introduction: Behavioral Parent Training (BPT) is often provided for childhood psychiatric disorders. These disorders have been shown to be associated with working memory impairments. BPT is based on operant learning principles, yet how operant principles shape behavior (through the partial reinforcement (PRF) extinction effect, i.e., greater resistance to extinction that is created when behavior is reinforced partially rather than continuously) and the potential role of working memory therein is scarcely studied in children. This study explored the PRF extinction effect and the role of working memory therein using experimental tasks in typically developing children. Methods: Ninety-seven children (age 6–10) completed a working memory task and an operant learning task, in which children acquired a response-sequence rule under either continuous or PRF (120 trials), followed by an extinction phase (80 trials). Data of 88 children were used for analysis. Results: The PRF extinction effect was confirmed: We observed slower acquisition and extinction in the PRF condition as compared to the continuous reinforcement (CRF) condition. Working memory was negatively related to acquisition but not extinction performance. Conclusion: Both reinforcement contingencies and working memory relate to acquisition performance. Potential implications for BPT are that decreasing working memory load may enhance the chance of optimally learning through reinforcement. PMID:29643822

The effect of phosphodiesterase inhibitors on the extinction of cocaine-induced conditioned place preference in mice.

PubMed

Liddie, Shervin; Anderson, Karen L; Paz, Andres; Itzhak, Yossef

2012-10-01

Several phosphodiesterase inhibitors (PDEis) improve cognition, suggesting that an increase in brain cAMP and cGMP facilitates learning and memory. Since extinction of drug-seeking behavior requires associative learning, consolidation and formation of new memory, the present study investigated the efficacy of three different PDEis in the extinction of cocaine-induced conditioned place preference (CPP) in B6129S mice. Mice were conditioned by escalating doses of cocaine which was resistant to extinction by free exploration. Immediately following each extinction session mice received (a) saline/vehicle, (b) rolipram (PDE4 inhibitor), (c) BAY-73-6691 (PDE9 inhibitor) or (d) papaverine (PDE10A inhibitor). Mice that received saline/vehicle during extinction training showed no reduction in CPP for >10 days. BAY-73-6691 (a) dose-dependently increased cGMP in hippocampus and amygdala, (b) significantly facilitated extinction and (c) diminished the reinstatement of cocaine CPP. Rolipram, which selectively increased brain cAMP levels, and papaverine which caused increases in both cAMP and cGMP levels, had no significant effect on the extinction of cocaine CPP. The results suggest that increase in hippocampal and amygdalar cGMP levels via blockade of PDE9 has a prominent role in the consolidation of extinction learning.

Preventing the return of fear memories with postretrieval extinction: A human study using a burst of white noise as an aversive stimulus.

PubMed

Fernandez-Rey, Jose; Gonzalez-Gonzalez, Daniel; Redondo, Jaime

2018-06-07

Standard extinction procedures seem to imply an inhibition of the fear response, but not a modification of the original fear-memory trace, which remains intact (Bouton, 2002, 2004). Typically, the behavioral procedure used to modify this trace is the so-called postretrieval extinction, consisting of fear-memory reactivation followed by extinction applied within the reconsolidation window. However, the application of this technique yields mixed results, probably due to a series of boundary conditions that limit the effectiveness of postretrieval-extinction effects. In this study a number of potential, and hitherto unexplored, moderators of such effects are considered. Using an interval of 48 hr between extinction and re-extinction, the findings show a spontaneous recovery similar to that found in studies that use a 24-hr interval. Also, the use of intervals of 10 and 20 min between reactivation and extinction led to a similar fear return. Finally, the burst of white noise used as an unconditioned stimulus (US) here was shown to be as effective as the electric shock normally used in the study of fear-memory reconsolidation. These findings suggest that postretrieval extinction is an effective behavioral technique for modifying the original fear memory and for the elimination of the fear return. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Immediate Extinction Causes a Less Durable Loss of Performance than Delayed Extinction following Either Fear or Appetitive Conditioning

ERIC Educational Resources Information Center

Woods, Amanda M.; Bouton, Mark E.

2008-01-01

Five experiments with rat subjects compared the effects of immediate and delayed extinction on the durability of extinction learning. Three experiments examined extinction of fear conditioning (using the conditioned emotional response method), and two experiments examined extinction of appetitive conditioning (using the food-cup entry method). In…

Education as a tool for addressing the extinction crisis: moving students from understanding to action.

PubMed

Moyer-Horner, Lucas; Kirby, Rebecca; Vaughan, Christopher

2010-12-01

Human activity is leading to mass species extinctions worldwide. Conservation biology (CB) courses, taught worldwide at universities, typically focus on the proximal causes of extinction without teaching students how to respond to this crisis. The Extinction of Species 360 course has been taught yearly each fall semester to several hundred students at the University of Wisconsin-Madison for over two decades. In 2007 the instructor and five teaching assistants combined principles driving extinctions, based on traditional lectures and discussion sections, with action-oriented education targeting individual consumer habits, to a group of 285 students. Students learn the science underpinning conservation efforts, as evidenced by highly significant learning (< .001) gains in a 22 question survey in every measured category, and also make direct and immediate changes in their lifestyle and consumption habits. This course succeeded in each of its three primary goals: a) informed students about the value of and threats to biodiversity, similar to traditional CB courses, b) emphasized our personal role (as consumers) in perpetuating the extinction crisis and c) facilitated activities to reduce our impact and help alleviate the crisis. The results suggested students learned CB concepts and understood biodiversity's value, increased their awareness of the connection between personal consumption and extinction, and reduced their collective ecological footprints. Furthermore, students complemented their learning and multiplied the potential for consumption reduction, by participating in action-based activities. Such academic courses can provide a rigorous treatment of the direct and indirect causes of extinction while developing a student's sense of personal empowerment to help slow the extinction crisis.

Prefrontal Cortex KCa2 Channels Regulate mGlu5-Dependent Plasticity and Extinction of Alcohol-Seeking Behavior.

PubMed

Cannady, Reginald; McGonigal, Justin T; Newsom, Ryan J; Woodward, John J; Mulholland, Patrick J; Gass, Justin T

2017-04-19

Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu 5 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (K Ca 2) channels have also been implicated in extinction learning of fear memories, and mGlu 5 receptor activation can reduce K Ca 2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined K Ca 2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats. This study also explored related neuronal and synaptic mechanisms within the IL-PFC that underlie mGlu 5 -dependent enhancement of extinction learning. Using whole-cell patch-clamp electrophysiology, activation of mGlu 5 in ex vivo slices significantly reduced K Ca 2 channel currents in layer V IL-PFC pyramidal neurons, confirming functional downregulation of K Ca 2 channel activity by mGlu 5 receptors. Additionally, positive modulation of K Ca 2 channels prevented mGlu 5 receptor-dependent facilitation of long-term potentiation in the IL-PFC. Systemic and intra-IL-PFC treatment with apamin (K Ca 2 channel allosteric inhibitor) significantly enhanced extinction of alcohol-seeking behavior across multiple extinction sessions, an effect that persisted for 3 weeks, but was not observed after apamin microinfusions into the prelimbic PFC. Positive modulation of IL-PFC K Ca 2 channels significantly attenuated mGlu 5 -dependent facilitation of alcohol cue-conditioned extinction learning. These data suggest that mGlu 5 -dependent facilitation of extinction learning and synaptic plasticity in the IL-PFC involves functional inhibition of K Ca 2 channels. Moreover, these findings demonstrate that K Ca 2 channels are a novel target to facilitate long-lasting extinction of alcohol-seeking behavior. SIGNIFICANCE STATEMENT Alcohol use disorder is a chronic relapsing disorder that is associated with compulsive alcohol-seeking behavior. One of the main causes of alcohol relapse is the craving caused by environmental cues that are associated with alcohol. These cues are formed by normal learning and memory principles, and the understanding of the brain mechanisms that help form these associations can lead to the development of drugs and/or behavior therapies that reduce the impact that these cues have on relapse in alcoholics. Copyright © 2017 the authors 0270-6474/17/374359-11$15.00/0.

Contextual control of conditioning is not affected by extinction in a behavioral task with humans.

PubMed

Nelson, James Byron; Lamoureux, Jeffrey A

2015-06-01

The Attentional Theory of Context Processing (ATCP) states that extinction will arouse attention to contexts resulting in learning becoming contextually controlled. Participants learned to suppress responding to colored sensors in a video-game task where contexts were provided by different gameplay backgrounds. Four experiments assessed the contextual control of simple excitatory learning acquired to a test stimulus (T) after (Exp. 1) or during (Exp. 2-4) extinction of another stimulus (X). Experiment 1 produced no evidence of contextual control of T, though renewal to X was present both at the time T was trained and tested. In Experiment 2 no contextual control of T was evident when X underwent extensive conditioning and extinction. In Experiment 3 no contextual control of T was evident after extensive conditioning and extinction of X, and renewal to X was present. In Experiment 4 contextual control was evident to T, but it neither depended upon nor was enhanced by extinction of X. The results presented here appear to limit the generality of ATCP.

Immediate extinction causes a less durable loss of performance than delayed extinction following either fear or appetitive conditioning.

PubMed

Woods, Amanda M; Bouton, Mark E

2008-12-01

Five experiments with rat subjects compared the effects of immediate and delayed extinction on the durability of extinction learning. Three experiments examined extinction of fear conditioning (using the conditioned emotional response method), and two experiments examined extinction of appetitive conditioning (using the food-cup entry method). In all experiments, conditioning and extinction were accomplished in single sessions, and retention testing took place 24 h after extinction. In both fear and appetitive conditioning, immediate extinction (beginning 10 min after conditioning) caused a faster loss of responding than delayed extinction (beginning 24 h after conditioning). However, immediate extinction was less durable than delayed extinction: There was stronger spontaneous recovery during the final retention test. There was also substantial renewal of responding when the physical context was changed between immediate extinction and testing (Experiment 1). The results suggest that, in these two widely used conditioning preparations, immediate extinction does not erase or depotentiate the original learning, and instead creates a less permanent reduction in conditioned responding. Results did not support the possibility that the strong recovery after immediate extinction was due to a mismatch in the recent "context" provided by the presence or absence of a recent conditioning experience. Several other accounts are considered.

Autophosphorylation of [alpha]CaMKII is Differentially Involved in New Learning and Unlearning Mechanisms of Memory Extinction

ERIC Educational Resources Information Center

Kimura, Ryoichi; Silva, Alcino J.; Ohno, Masuo

2008-01-01

Accumulating evidence indicates the key role of [alpha]-calcium/calmodulin-dependent protein kinase II ([alpha]CaMKII) in synaptic plasticity and learning, but it remains unclear how this kinase participates in the processing of memory extinction. Here, we investigated the mechanism by which [alpha]CaMKII may mediate extinction by using…

Distinct Contributions of the Basolateral Amygdala and the Medial Prefrontal Cortex to Learning and Relearning Extinction of Context Conditioned Fear

ERIC Educational Resources Information Center

Laurent, Vincent; Westbrook, R. Frederick

2008-01-01

We studied the roles of the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in learning and relearning to inhibit context conditioned fear (freezing) in extinction. In Experiment 1, pre-extinction BLA infusion of the NMDA receptor (NMDAr) antagonist, ifenprodil, impaired the development and retention of inhibition but…

AX+, BX- Discrimination Learning in the Fear-Potentiated Startle Paradigm: Possible Relevance to Inhibitory Fear Learning in Extinction

ERIC Educational Resources Information Center

Myers, Karyn M.; Davis, Michael

2004-01-01

The neural mechanisms of fear suppression most commonly are studied through the use of extinction, a behavioral procedure in which a feared stimulus (i.e., one previously paired with shock) is nonreinforced repeatedly, leading to a reduction or elimination of the fear response. Although extinction is perhaps the most convenient index of fear…

Context, Learning, and Extinction

ERIC Educational Resources Information Center

Gershman, Samuel J.; Blei, David M.; Niv, Yael

2010-01-01

A. Redish et al. (2007) proposed a reinforcement learning model of context-dependent learning and extinction in conditioning experiments, using the idea of "state classification" to categorize new observations into states. In the current article, the authors propose an interpretation of this idea in terms of normative statistical inference. They…

Extinction learning is slower, weaker and less context specific after alcohol

PubMed Central

Bisby, James A.; King, John A.; Sulpizio, Valentina; Degeilh, Fanny; Valerie Curran, H.; Burgess, Neil

2015-01-01

Alcohol is frequently involved in psychological trauma and often used by individuals to reduce fear and anxiety. We examined the effects of alcohol on fear acquisition and extinction within a virtual environment. Healthy volunteers were administered alcohol (0.4 g/kg) or placebo and underwent acquisition and extinction from different viewpoints of a virtual courtyard, in which the conditioned stimulus, paired with a mild electric shock, was centrally located. Participants returned the following day to test fear recall from both viewpoints of the courtyard. Skin conductance responses were recorded as an index of conditioned fear. Successful fear acquisition under alcohol contrasted with impaired extinction learning evidenced by persistent conditioned responses (Experiment 1). Participants’ impairments in extinction under alcohol correlated with impairments in remembering object-locations in the courtyard seen from one viewpoint when tested from the other viewpoint. Alcohol-induced extinction impairments were overcome by increasing the number of extinction trials (Experiment 2). However, a test of fear recall the next day showed persistent fear in the alcohol group across both viewpoints. Thus, alcohol impaired extinction rather than acquisition of fear, suggesting that extinction is more dependent than acquisition on alcohol-sensitive representations of spatial context. Overall, extinction learning under alcohol was slower, weaker and less context-specific, resulting in persistent fear at test that generalized to the extinction viewpoint. The selective effect on extinction suggests an effect of alcohol on prefrontal involvement, while the reduced context-specificity implicates the hippocampus. These findings have important implications for the use of alcohol by individuals with clinical anxiety disorders. PMID:26234587

Disorientation, confabulation, and extinction capacity: clues on how the brain creates reality.

PubMed

Nahum, Louis; Ptak, Radek; Leemann, Béatrice; Schnider, Armin

2009-06-01

Disorientation and confabulation often have a common course, independent of amnesia. Behaviorally spontaneous confabulation is the form in which patients act according to a false concept of reality; they fail to abandon action plans (anticipations) that do not pertain to the present situation. This continued enactment of previously valid but meanwhile invalidated anticipations can be conceived as deficient extinction capacity, that is, failure to integrate negative prediction errors into behavior. In this study, we explored whether disorientation and behaviorally spontaneous confabulation are associated with extinction failure. Twenty-five patients hospitalized for neurorehabilitation after first-ever brain injury who either had severe amnesia (n = 17), an orbitofrontal lesion (n = 14), or both (n = 6) were tested regarding disorientation (questionnaire) and performed an experimental task of association learning and extinction. Five patients were also classified as behaviorally spontaneous confabulators. Extinction capacity explained 66% of the variance of orientation in the whole group of patients (amnesics only, 56%; orbitofrontal group only, 90%), whereas association learning explained only 17% of the variance in the whole group (amnesics only, 7%; orbitofrontal group only, 16%). Also, extinction capacity, but not association learning, significantly distinguished between behaviorally spontaneous confabulators and all other subjects. Disorientation and behaviorally spontaneous confabulation are strongly and specifically associated with a failure of extinction, the ability to learn that previously appropriate anticipations no longer apply. Rather than invoking high-level monitoring processes, the human brain seems to make use of an ancient biological faculty-extinction-to keep thought and behavior in phase with reality.

A fundamental role for context in instrumental learning and extinction.

PubMed

Bouton, Mark E; Todd, Travis P

2014-05-01

The purpose of this article is to review recent research that has investigated the effects of context change on instrumental (operant) learning. The first part of the article discusses instrumental extinction, in which the strength of a reinforced instrumental behavior declines when reinforcers are withdrawn. The results suggest that extinction of either simple or discriminated operant behavior is relatively specific to the context in which it is learned: As in prior studies of Pavlovian extinction, ABA, ABC, and AAB renewal effects can all be observed. Further analysis supports the idea that the organism learns to refrain from making a specific response in a specific context, or in more formal terms, an inhibitory context-response association. The second part of the article then discusses research suggesting that the context also controls instrumental behavior before it is extinguished. Several experiments demonstrate that a context switch after either simple or discriminated operant training causes a decrement in the strength of the response. Over a range of conditions, the animal appears to learn a direct association between the context and the response. Under some conditions, it can also learn a hierarchical representation of context and the response-reinforcer relation. Extinction is still more context-specific than conditioning, as indicated by ABC and AAB renewal. Overall, the results establish that the context can play a significant role in both the acquisition and extinction of operant behavior. Copyright © 2014 Elsevier B.V. All rights reserved.

Open-field exposure facilitates consummatory extinction.

PubMed

Justel, Nadia; Psyrdellis, Mariana; Pautassi, Ricardo M

2016-12-07

During extinction, the organism learns that a conditioned stimulus or a conditioned response is no longer associated with an unconditioned stimulus, and as a consequence, a decrement in the response is presented. The exposure to novel situations (e.g. exploration of a novel open field) has been used widely to modulate (i.e. either enhance or deteriorate) learning and memory. The aim of the present study was to test whether open-field exposure could modulate consummatory extinction. The results indicated that open-field exposure accelerated the extinction response (i.e. experimental animals provided novelty exposure had lower consummatory behavior than control animals) when applied before - but not after - the first extinction trial, or when applied before the second extinction trial. The results suggest that environmental treatments such as novelty exposure provide a valuable, nonpharmacological alternative to potentially modulate extinction processes.

Dispositional cognitive reappraisal modulates the neural correlates of fear acquisition and extinction.

PubMed

Hermann, Andrea; Keck, Tanja; Stark, Rudolf

2014-09-01

Adverse learning experiences play a significant role in the etiology of anxiety disorders. However, not all individuals experiencing negative events develop heightened anxiety. This is possibly due to individual differences in the regulation of negative emotions associated with these negative events. Cognitive reappraisal is defined as reinterpreting an emotion-eliciting situation in a way that changes its emotional impact. A more frequent use of cognitive reappraisal in daily life has been shown to be more adaptive. However, no study to date examined the association of dispositional cognitive reappraisal with emotional learning, in order to elucidate individual differences in negative emotional responses towards aversive events. The goal of this functional magnetic resonance imaging (fMRI) study was to investigate the association of dispositional cognitive reappraisal with subjective, electrodermal and neural correlates of fear acquisition and extinction. Data of 41 healthy individuals, who participated in a socially relevant differential conditioning paradigm (acquisition and extinction learning: day 1, extinction recall: day 2), were acquired. Dispositional cognitive reappraisal was negatively associated with right insula, and hippocampus activation during acquisition. Furthermore, the reduction of self-reported conditioned fear during extinction learning as well as reduced insula and enhanced rostral anterior cingulate cortex activation during extinction learning was related to cognitive reappraisal. In addition, reduced recovery of conditioned arousal, reduced anterior cingulate and dorsomedial prefrontal cortex activation and enhanced ventromedial prefrontal cortex activation during extinction recall was observed in individuals with higher cognitive reappraisal scores. The results indicate that dispositional cognitive reappraisal modulates subjective and neural correlates of fear conditioning, probably leading to reduced acquisition and stronger extinction learning and recall. These results point to the important role of dispositional cognitive reappraisal in the development and modification of conditioned emotional responses and might further improve our understanding of anxiety disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

The role of the medial prefrontal cortex in trace fear extinction

PubMed Central

Kwapis, Janine L.; Jarome, Timothy J.

2015-01-01

The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that supports extinction of this memory has received very little attention. Recent research has indicated that trace fear extinction requires a different neural circuit than delay extinction; trace extinction requires the participation of the retrosplenial cortex, but not the amygdala, as noted in a previous study. Here, we tested the roles of the prelimbic and infralimbic regions of the medial prefrontal cortex in trace and delay fear extinction by blocking NMDA receptors during extinction learning. We found that the prelimbic cortex is necessary for trace, but not for delay fear extinction, whereas the infralimbic cortex is involved in both types of extinction. These results are consistent with the idea that trace fear associations require plasticity in multiple cortical areas for successful extinction. Further, the infralimbic cortex appears to play a role in extinction regardless of whether the animal was initially trained in trace or delay conditioning. Together, our results provide new information about how the neural circuits supporting trace and delay fear extinction differ. PMID:25512576

Context-dependent extinction of an appetitive operant conditioned response in infant rats.

PubMed

Orellana Barrera, Estefanía; Arias, Carlos; González, Felisa; Abate, Paula

2017-04-01

The present study evaluated context-dependent learning under an operant conditioning procedure in infant rats. Preweanling rats were trained in context A during postnatal days (PDs) 16 and 17 to learn an appetitive operant conditioning task, employing milk chocolate as appetitive reinforcer. On PD18 the operant response was extinguished in context A, or in an alternative context B. The change from context A to B between acquisition and extinction did not affect the number of responses during extinction, but slightly modified the shape of the extinction curve. On PD19, a renewal test conducted in context A clearly showed ABA-renewal of the extinguished operant response. These results add to the body of evidence indicating that infants are able to acquire and retain contextual information, and support the notion that extinction during this ontogenetic period involves new learning. © 2017 Wiley Periodicals, Inc.

Inactivation of the Infralimbic but Not the Prelimbic Cortex Impairs Consolidation and Retrieval of Fear Extinction

ERIC Educational Resources Information Center

Laurent, Vincent; Westbrook, R. Frederick

2009-01-01

Rats were subjected to one or two cycles of context fear conditioning and extinction to study the roles of the prelimbic cortex (PL) and infralimbic cortex (IL) in learning and relearning to inhibit fear responses. Inactivation of the PL depressed fear responses across the first or second extinction but did not impair learning or relearning fear…

Active Avoidance: Neural Mechanisms and Attenuation of Pavlovian Conditioned Responding.

PubMed

Boeke, Emily A; Moscarello, Justin M; LeDoux, Joseph E; Phelps, Elizabeth A; Hartley, Catherine A

2017-05-03

Patients with anxiety disorders often experience a relapse in symptoms after exposure therapy. Similarly, threat responses acquired during Pavlovian threat conditioning often return after extinction learning. Accordingly, there is a need for alternative methods to persistently reduce threat responding. Studies in rodents have suggested that exercising behavioral control over an aversive stimulus can persistently diminish threat responses, and that these effects are mediated by the amygdala, ventromedial prefrontal cortex, and striatum. In this fMRI study, we attempted to translate these findings to humans. Subjects first underwent threat conditioning. We then contrasted two forms of safety learning: active avoidance, in which participants could prevent the shock through an action, and yoked extinction, with shock presentation matched to the active condition, but without instrumental control. The following day, we assessed subjects' threat responses (measured by skin conductance) to the conditioned stimuli without shock. Subjects next underwent threat conditioning with novel stimuli. Yoked extinction subjects showed an increase in conditioned response to stimuli from the previous day, but the active avoidance group did not. Additionally, active avoidance subjects showed reduced conditioned responding during novel threat conditioning, but the extinction group did not. We observed between-group differences in striatal BOLD responses to shock omission in Avoidance/Extinction. These findings suggest a differential role for the striatum in human active avoidance versus extinction learning, and indicate that active avoidance may be more effective than extinction in persistently diminishing threat responses. SIGNIFICANCE STATEMENT Extinguished threat responses often reemerge with time, highlighting the importance of identifying more enduring means of attenuation. We compared the effects of active avoidance learning and yoked extinction on threat responses in humans and contrasted the neural circuitry engaged by these two processes. Subjects who learned to prevent a shock through an action maintained low threat responses after safety learning and showed attenuated threat conditioning with novel stimuli, in contrast to those who underwent yoked extinction. The results suggest that experiences of active control over threat engage the striatum and promote a shift from expression of innate defensive responses toward more adaptive behavioral responses to threatening stimuli. Copyright © 2017 the authors 0270-6474/17/374808-11$15.00/0.

Active Avoidance: Neural Mechanisms and Attenuation of Pavlovian Conditioned Responding

PubMed Central

Boeke, Emily A.; Moscarello, Justin M.; Phelps, Elizabeth A.

2017-01-01

Patients with anxiety disorders often experience a relapse in symptoms after exposure therapy. Similarly, threat responses acquired during Pavlovian threat conditioning often return after extinction learning. Accordingly, there is a need for alternative methods to persistently reduce threat responding. Studies in rodents have suggested that exercising behavioral control over an aversive stimulus can persistently diminish threat responses, and that these effects are mediated by the amygdala, ventromedial prefrontal cortex, and striatum. In this fMRI study, we attempted to translate these findings to humans. Subjects first underwent threat conditioning. We then contrasted two forms of safety learning: active avoidance, in which participants could prevent the shock through an action, and yoked extinction, with shock presentation matched to the active condition, but without instrumental control. The following day, we assessed subjects' threat responses (measured by skin conductance) to the conditioned stimuli without shock. Subjects next underwent threat conditioning with novel stimuli. Yoked extinction subjects showed an increase in conditioned response to stimuli from the previous day, but the active avoidance group did not. Additionally, active avoidance subjects showed reduced conditioned responding during novel threat conditioning, but the extinction group did not. We observed between-group differences in striatal BOLD responses to shock omission in Avoidance/Extinction. These findings suggest a differential role for the striatum in human active avoidance versus extinction learning, and indicate that active avoidance may be more effective than extinction in persistently diminishing threat responses. SIGNIFICANCE STATEMENT Extinguished threat responses often reemerge with time, highlighting the importance of identifying more enduring means of attenuation. We compared the effects of active avoidance learning and yoked extinction on threat responses in humans and contrasted the neural circuitry engaged by these two processes. Subjects who learned to prevent a shock through an action maintained low threat responses after safety learning and showed attenuated threat conditioning with novel stimuli, in contrast to those who underwent yoked extinction. The results suggest that experiences of active control over threat engage the striatum and promote a shift from expression of innate defensive responses toward more adaptive behavioral responses to threatening stimuli. PMID:28408411

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors.

PubMed

Abraham, Antony D; Neve, Kim A; Lattal, K Matthew

2016-07-01

Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.

Regulation of Fear Extinction in the Basolateral Amygdala by Dopamine D2 Receptors Accompanied by Altered GluR1, GluR1-Ser845 and NR2B Levels.

PubMed

Shi, Yan-Wei; Fan, Bu-Fang; Xue, Li; Wen, Jia-Ling; Zhao, Hu

2017-01-01

The amygdala, a critical structure for both Pavlovian fear conditioning and fear extinction, receives sparse but comprehensive dopamine innervation and contains dopamine D1 and D2 receptors. Fear extinction, which involves learning to suppress the expression of a previously learned fear, appears to require the dopaminergic system. The specific roles of D2 receptors in mediating associative learning underlying fear extinction require further study. Intra-basolateral amygdala (BLA) infusions of a D2 receptor agonist, quinpirole, and a D2 receptor antagonist, sulpiride, prior to fear extinction and extinction retention were tested 24 h after fear extinction training for long-term memory (LTM). LTM was facilitated by quinpirole and attenuated by sulpiride. In addition, A-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor glutamate receptor 1 (GluR1) subunit, GluR1 phospho-Ser845, and N -methyl-D-aspartic acid receptor NR2B subunit levels in the BLA were generally increased by quinpirole and down-regulated by sulpiride. The present study suggests that activation of D2 receptors facilitates fear extinction and that blockade of D2 receptors impairs fear extinction, accompanied by changes in GluR1, GluR1-Ser845 and NR2B levels in the amygdala.

Dissociation of the Role of Infralimbic Cortex in Learning and Consolidation of Extinction of Recent and Remote Aversion Memory

PubMed Central

Awad, Walaa; Ferreira, Guillaume; Maroun, Mouna

2015-01-01

Medial prefrontal circuits have been reported to undergo a major reorganization over time and gradually take a more important role for remote emotional memories such as contextual fear memory or food aversion memory. The medial prefrontal cortex, and specifically its ventral subregion, the infralimbic cortex (IL), was also reported to be critical for recent memory extinction of contextual fear conditioning and conditioned odor aversion. However, its exact role in the extinction of remotely acquired information is still not clear. Using postretrieval blockade of protein synthesis or inactivation of the IL, we showed that the IL is similarly required for extinction consolidation of recent and remote fear memory. However, in odor aversion memory, the IL was only involved in extinction consolidation of recent, but not remote, memory. In contrast, only remote retrieval of aversion memory induced c-Fos activation in the IL and preretrieval inactivation of the IL with lidocaine impaired subsequent extinction of remote but not recent memory, indicating IL is necessary for extinction learning of remote aversion memory. In contrast to the effects in odor aversion, our data show that the involvement of the IL in the consolidation of fear extinction does not depend on the memory age. More importantly, our data indicate that the IL is implicated in the extinction of fear and nonfear-based associations and suggest dissociation in the engagement of the IL in the learning and consolidation of food aversion extinction over time. PMID:25872918

Evidence for recovery of fear following immediate extinction in rats and humans

PubMed Central

Schiller, Daniela; Cain, Christopher K.; Curley, Nina G.; Schwartz, Jennifer S.; Stern, Sarah A.; LeDoux, Joseph E.; Phelps, Elizabeth A.

2008-01-01

Fear responses can be eliminated through extinction, a procedure involving the presentation of fear-eliciting stimuli without aversive outcomes. Extinction is believed to be mediated by new inhibitory learning that acts to suppress fear expression without erasing the original memory trace. This hypothesis is supported mainly by behavioral data demonstrating that fear can recover following extinction. However, a recent report by Myers and coworkers suggests that extinction conducted immediately after fear learning may erase or prevent the consolidation of the fear memory trace. Since extinction is a major component of nearly all behavioral therapies for human fear disorders, this finding supports the notion that therapeutic intervention beginning very soon after a traumatic event will be more efficacious. Given the importance of this issue, and the controversy regarding immediate versus delayed therapeutic interventions, we examined two fear recovery phenomena in both rats and humans: spontaneous recovery (SR) and reinstatement. We found evidence for SR and reinstatement in both rats and humans even when extinction was conducted immediately after fear learning. Thus, our data do not support the hypothesis that immediate extinction erases the original memory trace, nor do they suggest that a close temporal proximity of therapeutic intervention to the traumatic event might be advantageous. PMID:18509113

Behavioral and neural bases of extinction learning in Hermissenda

PubMed Central

Cavallo, Joel S.; Hamilton, Brittany N.; Farley, Joseph

2014-01-01

Extinction of classical conditioning is thought to produce new learning that masks or interferes with the original memory. However, research in the nudibranch Hermissenda crassicornis (H.c.) has challenged this view, and instead suggested that extinction erased the original associative memory. We have re-examined extinction in H.c. to test whether extinguished associative memories can be detected on the behavioral and cellular levels, and to characterize the temporal variables involved. Associative conditioning using pairings of light (CS) and rotation (US) produced characteristic suppression of H.c. phototactic behavior. A single session of extinction training (repeated light-alone presentations) reversed suppressed behavior back to pre-training levels when administered 15 min after associative conditioning. This effect was abolished if extinction was delayed by 23 h, and yet was recovered using extended extinction training (three consecutive daily extinction sessions). Extinguished phototactic suppression did not spontaneously recover at any retention interval (RI) tested (2-, 24-, 48-, 72-h), or after additional US presentations (no observed reinstatement). Extinction training (single session, 15 min interval) also reversed the pairing-produced increases in light-evoked spike frequencies of Type B photoreceptors, an identified site of associative memory storage that is causally related to phototactic suppression. These results suggest that the behavioral effects of extinction training are not due to temporary suppression of associative memories, but instead represent a reversal of the underlying cellular changes necessary for the expression of learning. In the companion article, we further elucidate mechanisms responsible for extinction-produced reversal of memory-related neural plasticity in Type B photoreceptors. PMID:25191236

Plasticity of Fear and Safety Neurons of the Amygdala in Response to Fear Extinction

PubMed Central

Sangha, Susan

2015-01-01

Fear inhibition learning induces plasticity and remodeling of circuits within the amygdala. Most studies examine these changes in nondiscriminative fear conditioning paradigms. Using a discriminative fear, safety, and reward conditioning task, Sangha et al. (2013) have previously reported several neural microcircuits within the basal amygdala (BA) which discriminate among these cues, including a subpopulation of neurons responding selectively to a safety cue and not a fear cue. Here, the hypothesis that these “safety” neurons isolated during discriminative conditioning are biased to become fear cue responsive as a result of extinction, when fear behavior diminishes, was tested. Although 41% of “safety” neurons became fear cue responsive as a result of extinction, the data revealed that there was no bias for these neurons to become preferentially responsive during fear extinction compared to the other identified subgroups. In addition to the plasticity seen in the “safety” neurons, 44% of neurons unresponsive to either the fear cue or safety cue during discriminative conditioning became fear cue responsive during extinction. Together these emergent responses to the fear cue as a result of extinction support the hypothesis that new learning underlies extinction. In contrast, 47% of neurons responsive to the fear cue during discriminative conditioning became unresponsive to the fear cue during extinction. These findings are consistent with a suppression of neural responding mediated by inhibitory learning, or, potentially, by direct unlearning. Together, the data support extinction as an active process involving both gains and losses of responses to the fear cue and suggests the final output of the integrated BA circuit in influencing fear behavior is a balance of excitation and inhibition, and perhaps reversal of learning-induced changes. PMID:26733838

2-arachidonoylglycerol signaling impairs short-term fear extinction

PubMed Central

Hartley, N D; Gunduz-Cinar, O; Halladay, L; Bukalo, O; Holmes, A; Patel, S

2016-01-01

Impairments in fear extinction are thought to be central to the psychopathology of posttraumatic stress disorder, and endocannabinoid (eCB) signaling has been strongly implicated in extinction learning. Here we utilized the monoacylglycerol lipase inhibitor JZL184 to selectively augment brain 2-AG levels combined with an auditory cue fear-conditioning paradigm to test the hypothesis that 2-AG-mediated eCB signaling modulates short-term fear extinction learning in mice. We show that systemic JZL184 impairs short-term extinction learning in a CB1 receptor-dependent manner without affecting non-specific freezing behavior or the acquisition of conditioned fear. This effect was also observed in over-conditioned mice environmentally manipulated to re-acquire fear extinction. Cumulatively, the effects of JZL184 appear to be partly due to augmentation of 2-AG signaling in the basolateral nucleus of the amygdala (BLA), as direct microinfusion of JZL184 into the BLA produced similar results. Moreover, we elucidate a short ~3-day temporal window during which 2-AG augmentation impairs extinction behavior, suggesting a preferential role for 2-AG-mediated eCB signaling in the modulation of short-term behavioral sequelae to acute traumatic stress exposure. PMID:26926885

Enhanced Extinction of Aversive Memories by High-Frequency Stimulation of the Rat Infralimbic Cortex

PubMed Central

Maroun, Mouna; Kavushansky, Alexandra; Holmes, Andrew; Wellman, Cara; Motanis, Helen

2012-01-01

Electrical stimulation of the rodent medial prefrontal cortex (mPFC), including the infralimbic cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion. PMID:22586453

Extinction learning, which consists of the inhibition of retrieval, can be learned without retrieval.

PubMed

de Carvalho Myskiw, Jociane; Furini, Cristiane Regina Guerino; Schmidt, Bianca; Ferreira, Flávia; Izquierdo, Ivan

2015-01-13

In the present study we test the hypothesis that extinction is not a consequence of retrieval in unreinforced conditioned stimulus (CS) presentation but the mere perception of the CS in the absence of a conditioned response. Animals with cannulae implanted in the CA1 region of hippocampus were subjected to extinction of contextual fear conditioning. Muscimol infused intra-CA1 before an extinction training session of contextual fear conditioning (CFC) blocks retrieval but not consolidation of extinction measured 24 h later. Additionally, this inhibition of retrieval does not affect early persistence of extinction when tested 7 d later or its spontaneous recovery after 2 wk. Furthermore, both anisomycin, an inhibitor of ribosomal protein synthesis, and rapamycin, an inhibitor of extraribosomal protein synthesis, given into the CA1, impair extinction of CFC regardless of whether its retrieval was blocked by muscimol. Therefore, retrieval performance in the first unreinforced session is not necessary for the installation, maintenance, or spontaneous recovery of extinction of CFC.

Neural signals of vicarious extinction learning

PubMed Central

Haaker, Jan; Selbing, Ida; Olsson, Andreas

2016-01-01

Social transmission of both threat and safety is ubiquitous, but little is known about the neural circuitry underlying vicarious safety learning. This is surprising given that these processes are critical to flexibly adapt to a changeable environment. To address how the expression of previously learned fears can be modified by the transmission of social information, two conditioned stimuli (CS + s) were paired with shock and the third was not. During extinction, we held constant the amount of direct, non-reinforced, exposure to the CSs (i.e. direct extinction), and critically varied whether another individual—acting as a demonstrator—experienced safety (CS + vic safety) or aversive reinforcement (CS + vic reinf). During extinction, ventromedial prefrontal cortex (vmPFC) responses to the CS + vic reinf increased but decreased to the CS + vic safety. This pattern of vmPFC activity was reversed during a subsequent fear reinstatement test, suggesting a temporal shift in the involvement of the vmPFC. Moreover, only the CS + vic reinf association recovered. Our data suggest that vicarious extinction prevents the return of conditioned fear responses, and that this efficacy is reflected by diminished vmPFC involvement during extinction learning. The present findings may have important implications for understanding how social information influences the persistence of fear memories in individuals suffering from emotional disorders. PMID:27278792

Potentiation of GluN2C/D NMDA receptor subtypes in the amygdala facilitates the retention of fear and extinction learning in mice.

PubMed

Ogden, Kevin K; Khatri, Alpa; Traynelis, Stephen F; Heldt, Scott A

2014-02-01

NMDA receptors are glutamate receptor ion channels that contribute to synaptic plasticity and are important for many forms of learning and memory. In the amygdala, NMDA receptors are critical for the acquisition, retention, and extinction of classically conditioned fear responses. Although the GluN2B subunit has been implicated in both the acquisition and extinction of conditioned fear, GluN2C-knockout mice show reduced conditioned fear responses. Moreover, D-cycloserine (DCS), which facilitates fear extinction, selectively enhances the activity of GluN2C-containing NMDA receptors. To further define the contribution of GluN2C receptors to fear learning, we infused the GluN2C/GluN2D-selective potentiator CIQ bilaterally into the basolateral amygdala (3, 10, or 30 μg/side) following either fear conditioning or fear extinction training. CIQ both increased the expression of conditioned fear 24 h later and enhanced the extinction of the previously conditioned fear response. These results support a critical role for GluN2C receptors in the amygdala in the consolidation of learned fear responses and suggest that increased activity of GluN2C receptors may underlie the therapeutic actions of DCS.

Effects of chronic stress in adolescence on learned fear, anxiety, and synaptic transmission in the rat prelimbic cortex.

PubMed

Negrón-Oyarzo, Ignacio; Pérez, Miguel Ángel; Terreros, Gonzalo; Muñoz, Pablo; Dagnino-Subiabre, Alexies

2014-02-01

The prelimbic cortex and amygdala regulate the extinction of conditioned fear and anxiety, respectively. In adult rats, chronic stress affects the dendritic morphology of these brain areas, slowing extinction of learned fear and enhancing anxiety. The aim of this study was to determine whether rats subjected to chronic stress in adolescence show changes in learned fear, anxiety, and synaptic transmission in the prelimbic cortex during adulthood. Male Sprague Dawley rats were subjected to seven days of restraint stress on postnatal day forty-two (PND 42, adolescence). Afterward, the fear-conditioning paradigm was used to study conditioned fear extinction. Anxiety-like behavior was measured one day (PND 50) and twenty-one days (PND 70, adulthood) after stress using the elevated-plus maze and dark-light box tests, respectively. With another set of rats, excitatory synaptic transmission was analyzed with slices of the prelimbic cortex. Rats that had been stressed during adolescence and adulthood had higher anxiety-like behavior levels than did controls, while stress-induced slowing of learned fear extinction in adolescence was reversed during adulthood. As well, the field excitatory postsynaptic potentials of stressed adolescent rats had significantly lower amplitudes than those of controls, although the amplitudes were higher in adulthood. Our results demonstrate that short-term stress in adolescence induces strong effects on excitatory synaptic transmission in the prelimbic cortex and extinction of learned fear, where the effect of stress on anxiety is more persistent than on the extinction of learned fear. These data contribute to the understanding of stress neurobiology. Copyright © 2013 Elsevier B.V. All rights reserved.

Systemic or Intra-Amygdala Infusion of the Benzodiazepine, Midazolam, Impairs Learning, but Facilitates Re-Learning to Inhibit Fear Responses in Extinction

ERIC Educational Resources Information Center

Hart, Genevra; Harris, Justin A.; Westbrook, R. Frederick

2010-01-01

A series of experiments used rats to study the effect of a systemic or intra-amygdala infusion of the benzodiazepine, midazolam, on learning and re-learning to inhibit context conditioned fear (freezing) responses. Rats were subjected to two context-conditioning episodes followed by extinction under drug or vehicle, or to two cycles of context…

From resilience to vulnerability: mechanistic insights into the effects of stress on transitions in critical period plasticity.

PubMed

Callaghan, Bridget L; Graham, Bronwyn M; Li, Stella; Richardson, Rick

2013-01-01

While early experiences are proposed to be important for the emergence of anxiety and other mental health problems, there is little empirical research examining the impact of such experiences on the development of emotional learning. Of the research that has been performed in this area, however, a complex picture has emerged in which the maturation of emotion circuits is influenced by the early experiences of the animal. For example, under typical laboratory rearing conditions infant rats rapidly forget learned fear associations (infantile amnesia) and express a form of extinction learning which is relapse-resistant (i.e., extinction in infant rats may be due to fear erasure). In contrast, adult rats exhibit very long-lasting memories of past learned fear associations, and express a form of extinction learning that is relapse-prone (i.e., the fear returns in a number of situations). However, when rats are reared under stressful conditions then they exhibit adult-like fear retention and extinction behaviors at an earlier stage of development (i.e., good retention of learned fear and relapse-prone extinction learning). In other words, under typical rearing conditions infant rats appear to be protected from exhibiting anxiety whereas after adverse rearing fear learning appears to make those infants more vulnerable to the later development of anxiety. While the effects of different experiences on infant rats' fear retention and extinction are becoming better documented, the mechanisms which mediate the early transition seen following stress remain unclear. Here we suggest that rearing stress may lead to an early maturation of the molecular and cellular signals shown to be involved in the closure of critical period plasticity in sensory modalities (e.g., maturation of GABAergic neurons, development of perineuronal nets), and speculate that these signals could be manipulated in adulthood to reopen infant forms of emotional learning (i.e., those that favor resilience).

Lesions of the lateral habenula facilitate active avoidance learning and threat extinction.

PubMed

Song, Mihee; Jo, Yong Sang; Lee, Yeon-Kyung; Choi, June-Seek

2017-02-01

The lateral habenula (LHb) is an epithalamic brain structure that provides strong projections to midbrain monoaminergic systems that are involved in motivation, emotion, and reinforcement learning. LHb neurons are known to convey information about aversive outcomes and negative prediction errors, suggesting a role in learning from aversive events. To test this idea, we examined the effects of electrolytic lesions of the LHb on signaled two-way active avoidance learning in which rats were trained to avoid an unconditioned stimulus (US) by taking a proactive shuttling response to an auditory conditioned stimulus (CS). The lesioned animals learned the avoidance response significantly faster than the control groups. In a separate experiment, we also investigated whether the LHb contributes to Pavlovian threat (fear) conditioning and extinction. Following paired presentations of the CS and the US, LHb-lesioned animals showed normal acquisition of conditioned response (CR) measured with freezing. However, extinction of the CR in the subsequent CS-only session was significantly faster. The enhanced performance in avoidance learning and in threat extinction jointly suggests that the LHb normally plays an inhibitory role in learning driven by absence of aversive outcomes. Copyright © 2016 Elsevier B.V. All rights reserved.

The effect of hippocampal NMDA receptor blockade by MK-801 on cued fear extinction.

PubMed

Zhang, Bo; Li, Chuan-Yu; Wang, Xiu-Song

2017-08-14

Extinction of conditioned fear has been suggested to be a new form of learning instead of erasure of what was originally learned, and the process is NMDA (N-methyl d-aspartate) receptor (NMDAR) dependent. Most of studies have so far revealed the important roles of NMDARs in the amygdala and medial prefrontal cortex (mPFC) in cued fear extinction. Although the ventral hippocampus has intimately reciprocal connections with the amygdala and mPFC, the role of its NMDARs in cued fear extinction remains unclear. The present experiment explored the issue by bilateral pre-extinction microinjection of the noncompetitive NMDAR antagonist MK-801 into the ventral hippocampus. Four groups of rats were given habituation, tone cued fear conditioning, fear extinction training and extinction test. Prior to extinction training, rats received bilateral infusions of either MK-801 (1.5, 3, or 6μg/0.5μl) or saline. Our results showed that MK-801 reduced freezing on the first trial of extinction training with no impact on within-session acquisition of extinction, and that the lower doses of MK-801 resulted in increased freezing on the extinction retrieval test. These findings suggest that ventral hippocampal NMDARs are necessary for the consolidation of tone cued fear extinction. Copyright © 2017 Elsevier B.V. All rights reserved.

Early life programming of innate fear and fear learning in adult female rats.

PubMed

Stevenson, Carl W; Meredith, John P; Spicer, Clare H; Mason, Rob; Marsden, Charles A

2009-03-02

The early rearing environment can impact on emotional reactivity and learning later in life. In this study the effects of neonatal maternal separation (MS) on innate fear and fear learning were assessed in the adult female rat. Pups were subjected to MS (360 min), brief handling (H; 15 min), or animal facility rearing (AFR) on post-natal days 2-14. In the first experiment, innate fear was tested in the open field. No differences between the early rearing groups were observed in unconditioned fear. In the second experiment, separate cohorts were used in a 3-day fear learning paradigm which tested the acquisition (Day 1), expression and extinction (both Day 2) of conditioning to an auditory cue; extinction recall was determined as well (Day 3). Contextual fear conditioning was also assessed prior to cue presentations on Days 2 and 3. Whereas MS attenuated the acquisition and expression of fear conditioning to the cue, H potentiated extinction learning. Cue-induced fear was reduced on Day 3, compared to Day 2, indicating that the recall of extinction learning was evident; however, no early rearing group differences in extinction recall were observed. Similarly, while contextual fear was decreased on Day 3, compared to Day 2, there were no differences between the early rearing groups on either day tested. The present findings of altered cue-conditioned fear learning, in the absence of innate fear changes, lend further support for the important role of the early rearing environment in mediating cognition in adulthood.

Inhibiting corticosterone synthesis during fear memory formation exacerbates cued fear extinction memory deficits within the single prolonged stress model.

PubMed

Keller, Samantha M; Schreiber, William B; Stanfield, Briana R; Knox, Dayan

2015-01-01

Using the single prolonged stress (SPS) animal model of post-traumatic stress disorder (PTSD), previous studies suggest that enhanced glucocorticoid receptor (GR) expression leads to cued fear extinction retention deficits. However, it is unknown how the endogenous ligand of GRs, corticosterone (CORT), may contribute to extinction retention deficits in the SPS model. Given that CORT synthesis during fear learning is critical for fear memory consolidation and SPS enhances GR expression, CORT synthesis during fear memory formation could strengthen fear memory in SPS rats by enhancing GR activation during fear learning. In turn, this could lead to cued fear extinction retention deficits. We tested the hypothesis that CORT synthesis during fear learning leads to cued fear extinction retention deficits in SPS rats by administering the CORT synthesis inhibitor metyrapone to SPS and control rats prior to fear conditioning, and observed the effect this had on extinction memory. Inhibiting CORT synthesis during fear memory formation in control rats tended to decrease cued freezing, though this effect never reached statistical significance. Contrary to our hypothesis, inhibiting CORT synthesis during fear memory formation disrupted extinction retention in SPS rats. This finding suggests that even though SPS exposure leads to cued fear extinction memory deficits, CORT synthesis during fear memory formation enhances extinction retention in SPS rats. This suggests that stress-induced CORT synthesis in previously stressed rats can be beneficial. Copyright © 2015 Elsevier B.V. All rights reserved.

Early life programming of fear conditioning and extinction in adult male rats.

PubMed

Stevenson, Carl W; Spicer, Clare H; Mason, Rob; Marsden, Charles A

2009-12-28

The early rearing environment programs corticolimbic function and neuroendocrine stress reactivity in adulthood. Although early environmental programming of innate fear has been previously examined, its impact on fear learning and memory later in life remains poorly understood. Here we examined the role of the early rearing environment in programming fear conditioning and extinction in adult male rats. Pups were subjected to maternal separation (MS; 360 min), brief handling (H; 15 min), or animal facility rearing (AFR) on post-natal days 2-14. As adults, animals were tested in a 3-day fear learning and memory paradigm which assessed the acquisition, expression and extinction of fear conditioning to an auditory cue; the recall of extinction was also assessed. In addition, contextual fear was assessed prior to cued extinction and its recall. We found that the acquisition of fear conditioning to the cue was modestly impaired by MS. However, no early rearing group differences were observed in cue-induced fear expression. In contrast, both the rate of extinction and extinction recall were attenuated by H. Finally, although contextual fear was reduced after extinction to the cue, no differences in context-induced fear were observed between the early rearing groups. These results add to a growing body of evidence supporting an important role for early environmental programming of fear conditioning and extinction. They also indicate that different early rearing conditions can program varying effects on distinct fear learning and memory processes in adulthood.

Persistent Prelimbic Cortex Activity Contributes to Enhanced Learned Fear Expression in Females

ERIC Educational Resources Information Center

Fenton, Georgina E.; Pollard, Amelia K.; Halliday, David M.; Mason, Rob; Bredy, Timothy W.; Stevenson, Carl W.

2014-01-01

Anxiety disorders, such as post-traumatic stress, are more prevalent in women and are characterized by impaired inhibition of learned fear and medial prefrontal cortex (mPFC) dysfunction. Here we examined sex differences in fear extinction and mPFC activity in rats. Females showed more learned fear expression during extinction and its recall, but…

Shaking that icky feeling: effects of extinction and counterconditioning on disgust-related evaluative learning.

PubMed

Engelhard, Iris M; Leer, Arne; Lange, Emma; Olatunji, Bunmi O

2014-09-01

Learned disgust appears to play an important role in certain anxiety disorders, and can be explained by the process of evaluative conditioning, in which an affective evaluative reaction evoked by an unconditional stimulus (US) is transferred to a conditional stimulus (CS). Much remains unknown about how disgust-related evaluative learning can be effectively eliminated. Study 1 of the present investigation examined the effects of extinction on reducing the negative evaluation of a CS that was acquired during disgust conditioning. Participants completed acquisition trials, with a disgusting picture as US and two neutral pictures as CS (CS+ was paired with the US; CS- was unpaired), followed by extinction trials ("CS only"; experimental condition) or a filler task (control condition). Extinction trials reduced acquired US expectancy to the CS+, but did not extinguish negative evaluations of the CS+. Study 2 examined the effects of counterconditioning on evaluative learned disgust. After disgust acquisition trials, counterconditioning trials followed in which the CS+ was paired with a pleasant US (experimental condition) or a filler task (control condition). Counterconditioning trials reduced acquired US expectancy to the CS+ and reduced evaluative conditioned disgust. Implications of the potential differential effects of extinction and counterconditioning on evaluative learning for exposure-based treatment of specific anxiety disorders are discussed. Copyright © 2014. Published by Elsevier Ltd.

Extinction of chained instrumental behaviors: Effects of consumption extinction on procurement responding

PubMed Central

Thrailkill, Eric A.; Bouton, Mark E.

2015-01-01

Operant behavior is typically organized into sequences of responses that eventually lead to a reinforcer. Response elements can be categorized as those that directly lead to reward consumption (i.e., a consumption response), and those that lead to the opportunity to make the consumption response (i.e., a procurement response). These responses often differ topographically and in terms of the discriminative stimuli that set the occasion for them. We have recently shown that extinction of the procurement response acts to weaken the specific associated consumption response, and that active inhibition of the procurement response is required for this effect. To expand the analysis of the associative structure of chains, the present experiments asked the reverse question of whether extinction of consumption behavior results in a decrease in the associated procurement response in a discriminated heterogeneous chain. In Experiment 1, extinction of consumption alone led to an attenuation of the associated procurement response only when rats were allowed to make the consumption response in extinction. Exposure to the consumption stimulus alone was not sufficient to produce weakened procurement responding. In Experiment 2, rats learned two distinct heterogeneous chains; extinction of one consumption response specifically weakened the procurement response associated with it. The results add to evidence suggesting that rats learn a highly specific associative structure in behavior chains, and emphasize the role of learning response inhibition in extinction. PMID:26276367

Extinction of chained instrumental behaviors: Effects of consumption extinction on procurement responding.

PubMed

Thrailkill, Eric A; Bouton, Mark E

2016-03-01

Operant behavior is typically organized into sequences of responses that eventually lead to a reinforcer. Response elements can be categorized as those that directly lead to reward consumption (i.e., a consumption response) and those that lead to the opportunity to make the consumption response (i.e., a procurement response). These responses often differ topographically and in terms of the discriminative stimuli that set the occasion for them. We have recently shown that extinction of the procurement response acts to weaken the specific associated consumption response, and that active inhibition of the procurement response is required for this effect. To expand the analysis of the associative structure of chains, in the present experiments we asked the reverse question: whether extinction of consumption behavior results in a decrease in the associated procurement response in a discriminated heterogeneous chain. In Experiment 1, extinction of consumption alone led to an attenuation of the associated procurement response only when rats were allowed to make the consumption response in extinction. Exposure to the consumption stimulus alone was not sufficient to produce weakened procurement responding. In Experiment 2, rats learned two distinct heterogeneous chains, and extinction of one consumption response specifically weakened the procurement response associated with it. The results add to the evidence suggesting that rats learn a highly specific associative structure in behavior chains, emphasizing the role of learning response inhibition in extinction.

Acute stress impairs the retrieval of extinction memory in humans

PubMed Central

Raio, Candace M.; Brignoni-Perez, Edith; Goldman, Rachel; Phelps, Elizabeth A.

2014-01-01

Extinction training is a form of inhibitory learning that allows an organism to associate a previously aversive cue with a new, safe outcome. Extinction does not erase a fear association, but instead creates a competing association that may or may not be retrieved when a cue is subsequently encountered. Characterizing the conditions under which extinction learning is expressed is important to enhancing the treatment of anxiety disorders that rely on extinction-based exposure therapy as a primary treatment technique. The ventromedial prefrontal cortex, which plays an important role in the expression of extinction memory, has been shown to be functionally impaired after stress exposure. Further, recent research in rodents found that exposure to stress led to deficits in extinction retrieval, although this has yet to be tested in humans. To explore how stress might influence extinction retrieval in humans, participants underwent a differential aversive learning paradigm, in which one image was probabilistically paired with an aversive shock while the other image denoted safety. Extinction training directly followed, at which point reinforcement was omitted. A day later, participants returned to the lab and either completed an acute stress manipulation (i.e., cold pressor), or a control task, before undergoing an extinction retrieval test. Skin conductance responses and salivary cortisol concentrations were measured throughout each session as indices of fear arousal and neuroendocrine stress responses, respectively. The efficacy of our stress induction was established by observing significant increases in cortisol for the stress condition only. We examined extinction retrieval by comparing conditioned responses during the last trial of extinction (day 1) with that of the first trial of re-extinction (day 2). Groups did not differ on initial fear acquisition or extinction, however, one day later participants in the stress group (n = 27) demonstrated significantly less extinction retrieval (i.e., greater fear recovery) than those in the control group (n = 25). Our results suggest that acute stress impairs extinction memory retrieval and offers insight into why treatment strategies used in the clinic may be challenging to recruit in daily life where stress is pervasive. PMID:24508065

Calcineurin inhibition blocks within-, but not between-session fear extinction in mice

PubMed Central

Moulin, Thiago C.; Carneiro, Clarissa F. D.; Gonçalves, Marina M. C.; Junqueira, Lara S.; Amaral, Olavo B.

2015-01-01

Memory extinction involves the formation of a new associative memory that inhibits a previously conditioned association. Nonetheless, it could also depend on weakening of the original memory trace if extinction is assumed to have multiple components. The phosphatase calcineurin (CaN) has been described as being involved in extinction but not in the initial consolidation of fear learning. With this in mind, we set to study whether CaN could have different roles in distinct components of extinction. Systemic treatment with the CaN inhibitors cyclosporin A (CsA) or FK-506, as well as i.c.v. administration of CsA, blocked within-session, but not between-session extinction or initial learning of contextual fear conditioning. Similar effects were found in multiple-session extinction of contextual fear conditioning and in auditory fear conditioning, indicating that CaN is involved in different types of short-term extinction. Meanwhile, inhibition of protein synthesis by cycloheximide (CHX) treatment did not affect within-session extinction, but disrupted fear acquisition and slightly impaired between-session extinction. Our results point to a dissociation of within- and between-session extinction of fear conditioning, with the former being more dependent on CaN activity and the latter on protein synthesis. Moreover, the modulation of within-session extinction did not affect between-session extinction, suggesting that these components are at least partially independent. PMID:25691516

Extinguishing trace fear engages the retrosplenial cortex rather than the amygdala

PubMed Central

Kwapis, Janine L.; Jarome, Timothy J.; Lee, Jonathan L.; Gilmartin, Marieke R.; Helmstetter, Fred J.

2013-01-01

Extinction learning underlies the treatment for a variety of anxiety disorders. Most of what is known about the neurobiology of extinction is based on standard “delay” fear conditioning, in which awareness is not required for learning. Little is known about how complex, explicit associations extinguish, however. “Trace” conditioning is considered to be a rodent model of explicit fear because it relies on both the cortex and hippocampus and requires explicit contingency awareness in humans. Here, we explore the neural circuit supporting trace fear extinction in order to better understand how complex memories extinguish. We first show that the amygdala is selectively involved in delay fear extinction; blocking intra-amygdala glutamate receptors disrupted delay, but not trace extinction. Further, ERK phosphorylation was increased in the amygdala after delay, but not trace extinction. We then identify the retrosplenial cortex (RSC) as a key structure supporting trace extinction. ERK phosphorylation was selectively increased in the RSC following trace extinction and blocking intra-RSC NMDA receptors impaired trace, but not delay extinction. These findings indicate that delay and trace extinction require different neural circuits; delay extinction requires plasticity in the amygdala whereas trace extinction requires the RSC. Anxiety disorders linked to explicit memory may therefore depend on cortical processes that have not been traditionally targeted by extinction studies based on delay fear. PMID:24055593

Applying extinction research and theory to cue-exposure addiction treatments.

PubMed

Conklin, Cynthia A; Tiffany, Stephen T

2002-02-01

To evaluate the efficacy of cue-exposure addiction treatment and review modern animal learning research to generate recommendations for substantially enhancing the effectiveness of this treatment. Meta-analysis of cue-exposure addiction treatment outcome studies (N=9), review of animal extinction research and theory, and evaluation of whether major principles from this literature are addressed adequately in cue-exposure treatments. The meta-analytical review showed that there is no consistent evidence for the efficacy of cue-exposure treatment as currently implemented. Moreover, procedures derived from the animal learning literature that should maximize the potential of extinction training are rarely used in cue-exposure treatments. Given what is known from animal extinction theory and research about extinguishing learned behavior, it is not surprising that cue-exposure treatments so often fail. This paper reviews current animal research regarding the most salient threats to the development and maintenance of extinction, and suggests several major procedures for increasing the efficacy of cue-exposure addiction treatment.

Biodiversity hotspots house most undiscovered plant species.

PubMed

Joppa, Lucas N; Roberts, David L; Myers, Norman; Pimm, Stuart L

2011-08-09

For most organisms, the number of described species considerably underestimates how many exist. This is itself a problem and causes secondary complications given present high rates of species extinction. Known numbers of flowering plants form the basis of biodiversity "hotspots"--places where high levels of endemism and habitat loss coincide to produce high extinction rates. How different would conservation priorities be if the catalog were complete? Approximately 15% more species of flowering plant are likely still undiscovered. They are almost certainly rare, and depending on where they live, suffer high risks of extinction from habitat loss and global climate disruption. By using a model that incorporates taxonomic effort over time, regions predicted to contain large numbers of undiscovered species are already conservation priorities. Our results leave global conservation priorities more or less intact, but suggest considerably higher levels of species imperilment than previously acknowledged.

Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy.

PubMed

MacPherson, Kathryn; Whittle, Nigel; Camp, Marguerite; Gunduz-Cinar, Ozge; Singewald, Nicolas; Holmes, Andrew

2013-07-05

Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. While there is growing evidence that fear extinction is influenced by certain procedural variables, it is unclear how these influences might vary across individuals and subpopulations. To model individual differences in fear extinction, prior studies identified a strain of inbred mouse, 129S1/SvImJ (S1), which exhibits a profound deficit in fear extinction, as compared to other inbred strains, such as C57BL/6J (B6). Here, we assessed the effects of procedural variables on the impaired extinction phenotype of the S1 strain and, by comparison, the extinction-intact B6 strain. The variables studied were 1) the interval between conditioning and extinction, 2) the interval between cues during extinction training, 3) single-cue exposure before extinction training, and 4) extinction of a second-order conditioned cue. Conducting extinction training soon after ('immediately') conditioning attenuated fear retrieval in S1 mice and impaired extinction in B6 mice. Spacing cue presentations with long inter-trial intervals during extinction training augmented fear in S1 and B6 mice. The effect of spacing was lost with one-trial fear conditioning in B6, but not S1 mice. A single exposure to a conditioned cue before extinction training did not alter extinction retrieval, either in B6 or S1 mice. Both the S1 and B6 strains exhibited robust second-order fear conditioning, in which a cue associated with footshock was sufficient to serve as a conditioned exciter to condition a fear association to a second cue. B6 mice extinguished the fear response to the second-order conditioned cue, but S1 mice failed to do so. These data provide further evidence that fear extinction is strongly influenced by multiple procedural variables and is so in a highly strain-dependent manner. This suggests that the efficacy of extinction-based behavioral interventions, such as exposure therapy, for trauma-related anxiety disorders will be determined by the procedural parameters employed and the degree to which the patient can extinguish.

Fear extinction can be made state-dependent on peripheral epinephrine: role of norepinephrine in the nucleus tractus solitarius.

PubMed

Rosa, Jessica; Myskiw, Jociane C; Furini, Cristiane R G; Sapiras, Gerson G; Izquierdo, Ivan

2014-09-01

We investigate whether the extinction of inhibitory avoidance (IA) learning can be subjected to endogenous state-dependence with systemic injections of epinephrine (E), and whether endogenous norepinephrine (NE) and the nucleus tractus solitarius (NTS)→locus coeruleus→hippocampus/amygdala (HIPP/BLA) pathway participate in this. Rats trained in IA were submitted to two sessions of extinction 24 h apart: In the first, the animals were submitted to a training session of extinction, and in the second they were tested for the retention of extinction. Saline or E were given i.p. immediately after the extinction training (post-extinction training injections) and/or 6 min before the extinction test (pre-extinction test). Post-extinction training E (50 or 100 μg/kg) induced a poor retrieval of extinction in the test session of this task unless an additional E injection (50 μg/kg) was given prior to the extinction test. This suggested state-dependence. Muscimol (0.01 μg/side) microinfused into the NTS prior to the extinction test session blocked E-induced state-dependence. Norepinephrine (NE, 1 μg/side) infused bilaterally into NTS restores the extinction impairment caused by post-extinction training i.p. E. In animals with bilateral NTS blockade induced by muscimol, NE (1 μg/side) given prior to the extinction test into the CA1 region of the dorsal hippocampus or into the basolateral amygdala restored the normal extinction levels that had been impaired by muscimol. These results suggest a role for the NTS→locus coeruleus→HIPP/BLA pathway in the retrieval of extinction, as it has been shown to have in the consolidation of inhibitory avoidance and of object recognition learning. Copyright © 2013 Elsevier Inc. All rights reserved.

The effects of compound stimulus extinction and inhibition of noradrenaline reuptake on the renewal of alcohol seeking

PubMed Central

Furlong, T M; Pan, M J; Corbit, L H

2015-01-01

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli can reduce their impact on relapse; however, the expression of extinction can be disrupted when testing occurs outside the context where extinction learning took place, an effect termed renewal. Behavioral and pharmacological methods have recently been shown to augment extinction learning; yet, it is not known whether the improved expression of extinction following these treatments remains context-dependent. Here we examined whether two methods, compound–stimulus extinction and treatment with the noradrenaline reuptake inhibitor atomoxetine, would reduce the vulnerability of extinction to a change in context. Following alcohol self-administration, responding was extinguished in a distinct context. After initial extinction, further extinction was given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg kg−1; Experiment 2). A stimulus extinguished as part of a compound elicited less responding than a stimulus receiving equal extinction alone regardless of whether animals were tested in the training or extinction context; however, reliable renewal was not observed in this paradigm. Importantly, atomoxetine enhanced extinction relative to controls even in the presence of a reliable renewal effect. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Importantly, both methods improve extinction even when the context is changed between extinction training and test, and thus could be utilized to enhance the outcome of extinction-based treatments for alcohol-use disorders. PMID:26327688

Fibroblast Growth Factor-2 Alters the Nature of Extinction

ERIC Educational Resources Information Center

Graham, Bronwyn M.; Richardson, Rick

2011-01-01

These experiments examined the effects of the NMDA-receptor (NMDAr) antagonist MK801 on reacquisition and re-extinction of a conditioned fear that had been previously extinguished before injection of fibroblast growth factor-2 (FGF2) or vehicle. Recent findings have shown that relearning and re-extinction, unlike initial learning and extinction,…

Behavioral and Neurobiological Mechanisms of Extinction in Pavlovian and Instrumental Learning

PubMed Central

Todd, Travis P.; Vurbic, Drina; Bouton, Mark E.

2013-01-01

This article reviews research on the behavioral and neural mechanisms of extinction as it is represented in both Pavlovian and instrumental learning. In Pavlovian extinction, repeated presentation of a signal without its reinforcer weakens behavior evoked by the signal; in instrumental extinction, repeated occurrence of a voluntary action without its reinforcer weakens the strength of the action. In either case, contemporary research at both the behavioral and neural levels of analysis has been guided by a set of extinction principles that were first generated by research conducted at the behavioral level. The review discusses these principles and illustrates how they have informed the study of both Pavlovian and instrumental extinction. It shows that behavioral and neurobiological research efforts have been tightly linked and that their results are readily integrated. Pavlovian and instrumental extinction are also controlled by compatible behavioral and neural processes. Since many behavioral effects observed in extinction can be multiply determined, we suggest that the current close connection between behavioral-level and neural-level analyses will need to continue. PMID:23999219

From lab to clinic: Extinction of cued cravings to reduce overeating.

PubMed

Jansen, Anita; Schyns, Ghislaine; Bongers, Peggy; van den Akker, Karolien

2016-08-01

Food cue reactivity is a strong motivation to eat, even in the absence of hunger. Therefore, food cue reactivity might sabotage healthy eating, induce weight gain and impede weight loss or weight maintenance. Food cue reactivity can be learned via Pavlovian appetitive conditioning: It is easily acquired but the extinction of appetitive responding seems to be more challenging. Several properties of extinction make it fragile: extinction does not erase the original learning and extinction is context-dependent. These properties threaten full extinction and increase the risk of full relapse. Extinction procedures are discussed to reduce or prevent the occurrence of rapid reacquisition, spontaneous recovery, renewal and reinstatement after extinction. A translation to food cue exposure treatment is made and suggestions are provided, such as conducting the exposure in relevant contexts, using occasional reinforcement and targeting expectancy violation instead of habituation. A new hypothesis proposed here is that the adding of inhibition training to strengthen inhibition skills that reduce instrumental responding, might be beneficial to improve food cue exposure effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Behavioral and neurobiological mechanisms of extinction in Pavlovian and instrumental learning.

PubMed

Todd, Travis P; Vurbic, Drina; Bouton, Mark E

2014-02-01

This article reviews research on the behavioral and neural mechanisms of extinction as it is represented in both Pavlovian and instrumental learning. In Pavlovian extinction, repeated presentation of a signal without its reinforcer weakens behavior evoked by the signal; in instrumental extinction, repeated occurrence of a voluntary action without its reinforcer weakens the strength of the action. In either case, contemporary research at both the behavioral and neural levels of analysis has been guided by a set of extinction principles that were first generated by research conducted at the behavioral level. The review discusses these principles and illustrates how they have informed the study of both Pavlovian and instrumental extinction. It shows that behavioral and neurobiological research efforts have been tightly linked and that their results are readily integrated. Pavlovian and instrumental extinction are also controlled by compatible behavioral and neural processes. Since many behavioral effects observed in extinction can be multiply determined, we suggest that the current close connection between behavioral-level and neural-level analyses will need to continue. Copyright © 2013 Elsevier Inc. All rights reserved.

Learning and extinction of a passive avoidance response in mice with high levels of predisposition to catalepsy.

PubMed

Dubrovina, N I; Zinov'ev, D R; Zinov'eva, D V; Kulikov, A V

2009-06-01

This report presents results obtained from comparative analysis of learning and the dynamics of extinction of a conditioned passive avoidance response in ASC mice, which were bred for a high level of predisposition to catalepsy, and in CBA and AKR mice. The following findings were obtained: 1) impairments to the extinction of the memory of fear represent an important symptom of depression in ASC mice; 2) extinction is delayed in CBA mice; and 3) new inhibitory learning occurs quickly in AKR mice. Prolonged retention of the fear memory in ASC mice appears to be related to increased anxiety on prolonged testing without a punishment. The deficit of inhibition of the fear reaction in ASC mice allows this strain to be regarded as a genetic model of depression.

Beta-adrenergic receptors support attention to extinction learning that occurs in the absence, but not the presence, of a context change

PubMed Central

André, Marion Agnès Emma; Wolf, Oliver T.; Manahan-Vaughan, Denise

2015-01-01

The noradrenergic (NA)-system is an important regulator of cognitive function. It contributes to extinction learning (EL), and in disorders where EL is impaired NA-dysfunction has been postulated. We explored whether NA acting on beta-adrenergic-receptors (β-AR), regulates EL that depends on context, but is not fear-associated. We assessed behavior in an “AAA” or “ABA” paradigm: rats were trained for 3 days in a T-maze (context-A) to learn that a reward is consistently found in the goal arm, despite low reward probability. This was followed on day 4 by EL (unrewarded), whereby in the ABA-paradigm, EL was reinforced by a context change (B), and in the AAA-paradigm, no context change occurred. On day 5, re-exposure to the A-context (unrewarded) occurred. Typically, in control “AAA” animals EL occurred on day 4 that progressed further on day 5. In control “ABA” animals, EL also occurred on day 4, followed by renewal of the previously learned (A) behavior on day 5, that was succeeded (on day 5) by extinction of this behavior, as the animals realised that no food reward would be given. Treatment with the β-AR-antagonist, propranolol, prior to EL on day 4, impaired EL in the AAA-paradigm. In the “ABA” paradigm, antagonist treatment on day 4, had no effect on extinction that was reinforced by a context change (B). Furthermore, β-AR-antagonism prior to renewal testing (on day 5) in the ABA-paradigm, resulted in normal renewal behavior, although subsequent extinction of responses during day 5 was prevented by the antagonist. Thus, under both treatment conditions, β-AR-antagonism prevented extinction of the behavior learned in the “A” context. β-AR-blockade during an overt context change did not prevent EL, whereas β-AR were required for EL in an unchanging context. These data suggest that β-AR may support EL by reinforcing attention towards relevant changes in the previously learned experience, and that this process supports extinction learning in constant-context conditions. PMID:26074793

Extinction memory is facilitated by methylphenidate and regulated by dopamine and noradrenaline receptors.

PubMed

Furini, Cristiane R G; Behling, Jonny A K; Zinn, Carolina G; Zanini, Mara Lise; Assis Brasil, Eduardo; Pereira, Luiza Doro; Izquierdo, Ivan; de Carvalho Myskiw, Jociane

2017-05-30

Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5μg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1μg/side) or MPH+SCH23390 (1.5μg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both β-adrenergic and D1/D5 dopaminergic receptors. Copyright © 2017 Elsevier B.V. All rights reserved.

Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor.

PubMed

Brenhouse, Heather C; Thompson, Britta S; Sonntag, Kai C; Andersen, Susan L

2015-08-01

Extinction of behaviors in response to drug-associated cues and prevention of reinstatement are integral for addiction treatment, and can reverse or ameliorate the harmful consequences of drug use. The mechanisms controlling extinction and reinstatement involve prefrontal cortical dopamine receptors, which change in expression and activity during the juvenile and adolescent transitions until they mature in adulthood. Little is known about the role that PFC D1 dopamine receptors play in extinction of drug-paired associations early in life. We used extinction of place preferences for cocaine in juvenile male and female rats following genetic, cell-specific overexpression of D1 on glutamatergic cells in the PFC. All subjects needed to demonstrate cocaine preferences for inclusion in the extinction studies. Here, male juveniles with a preference to 10 mg/kg cocaine took longer to extinguish preferences compared to both male adults and female juveniles. Female juveniles extinguished more rapidly than male juveniles at 20 mg/kg cocaine. Overexpression of D1 in juvenile males significantly facilitated extinction relative to juvenile male controls, whereas D1 prolonged expression of extinction in adults overexpressing D1 and adolescents who naturally have elevated D1 expression. These data suggest that an immature D1 profile in juveniles prevented the learning of new associations, and D1 overexpression may provide sufficient activity to facilitate extinction learning. D1 overexpression reduced reinstatement to a priming dose of cocaine in juvenile males. Together, these data show D1 expression may re-program motivational circuitry to facilitate extinction learning during juvenility that is normally unavailable to juveniles and that sex differences exist. Copyright © 2015 Elsevier Ltd. All rights reserved.

Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor

PubMed Central

Brenhouse, Heather C.; Thompson, Britta S.; Sonntag, Kai C.; Andersen, Susan L.

2015-01-01

Extinction of behaviors in response to drug-associated cues and prevention of reinstatement are integral for addiction treatment, and can reverse or ameliorate the harmful consequences of drug use. The mechanisms controlling extinction and reinstatement involve prefrontal cortical dopamine receptors, which change in expression and activity during the juvenile and adolescent transitions until they mature in adulthood. Little is known about the role that PFC D1 dopamine receptors play in extinction of drug-paired associations early in life. We used extinction of place preferences for cocaine in juvenile male and female rats following genetic, cell-specific overexpression of D1 on glutamatergic cells in the PFC. All subjects needed to demonstrate cocaine preferences for inclusion in the extinction studies. Here, male juveniles with a preference to 10 mg/kg cocaine took longer to extinguish preferences compared to both male adults and female juveniles. Female juveniles extinguished more rapidly than male juveniles at 20 mg/kg cocaine. Overexpression of D1 in juvenile males significantly facilitated extinction relative to juvenile male controls, whereas D1 prolonged expression of extinction in adults overexpressing D1 and adolescents who naturally have elevated D1 expression. These data suggest that an immature D1 profile in juveniles prevented the learning of new associations, and D1 overexpression may provide sufficient activity to facilitate extinction learning. D1 overexpression reduced reinstatement to a priming dose of cocaine in juvenile males. Together, these data show D1 expression may re-program motivational circuitry to facilitate extinction learning during juvenility that is normally unavailable to juveniles and that sex differences exist. PMID:25749358

Comparative effects of pulmonary and parenteral Δ⁹-tetrahydrocannabinol exposure on extinction of opiate-induced conditioned aversion in rats.

PubMed

Manwell, Laurie A; Mallet, Paul E

2015-05-01

Evidence suggesting that the endogenous cannabinoid (eCB) system can be manipulated to facilitate or impair extinction of learned behaviours has important consequences for opiate withdrawal and abstinence. We demonstrated that the fatty acid amide hydrolase (FAAH) inhibitor URB597, which increases eCB levels, facilitates extinction of a naloxone-precipitated morphine withdrawal-induced conditioned place aversion (CPA). The potential of the exogenous CB1 ligand, Δ(9)-tetrahydrocannabinol (Δ(9)-THC), to facilitate extinction of this CPA was tested. Effects of both pulmonary and parenteral Δ(9)-THC exposure were evaluated using comparable doses previously determined. Rats trained to associate a naloxone-precipitated morphine withdrawal with a floor cue were administered Δ(9)-THC-pulmonary (1, 5, 10 mg vapour inhalation) or parenteral (0.5, 1.0, 1.5 mg/kg intraperitoneal injection)-prior to each of 20 to 28 extinction/testing trials. Vapourized Δ(9)-THC facilitated extinction of the CPA in a dose- and time-dependent manner: 5 and 10 mg facilitated extinction compared to vehicle and 1 mg Δ(9)-THC. Injected Δ(9)-THC significantly impaired extinction only for the 1.0-mg/kg dose: it prolonged the CPA fourfold longer than the vehicle and 0.5- and 1.5-mg/kg doses. These data suggest that both dose and route of Δ(9)-THC administration have important consequences for its pharmacokinetic and behavioural effects; specifically, pulmonary exposure at higher doses facilitates, whereas pulmonary and parenteral exposure at lower doses impairs, rates of extinction learning for CPA. Pulmonary-administered Δ(9)-THC may prove beneficial for potentiation of extinction learning for aversive memories, such as those supporting drug-craving/seeking in opiate withdrawal syndrome, and other causes of conditioned aversions, such as illness and stress.

A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories

PubMed Central

Agis-Balboa, Roberto Carlos; Arcos-Diaz, Dario; Wittnam, Jessica; Govindarajan, Nambirajan; Blom, Kim; Burkhardt, Susanne; Haladyniak, Ulla; Agbemenyah, Hope Yao; Zovoilis, Athanasios; Salinas-Riester, Gabriella; Opitz, Lennart; Sananbenesi, Farahnaz; Fischer, Andre

2011-01-01

Extinction learning refers to the phenomenon that a previously learned response to an environmental stimulus, for example, the expression of an aversive behaviour upon exposure to a specific context, is reduced when the stimulus is repeatedly presented in the absence of a previously paired aversive event. Extinction of fear memories has been implicated with the treatment of anxiety disease but the molecular processes that underlie fear extinction are only beginning to emerge. Here, we show that fear extinction initiates upregulation of hippocampal insulin-growth factor 2 (Igf2) and downregulation of insulin-growth factor binding protein 7 (Igfbp7). In line with this observation, we demonstrate that IGF2 facilitates fear extinction, while IGFBP7 impairs fear extinction in an IGF2-dependent manner. Furthermore, we identify one cellular substrate of altered IGF2 signalling during fear extinction. To this end, we show that fear extinction-induced IGF2/IGFBP7 signalling promotes the survival of 17–19-day-old newborn hippocampal neurons. In conclusion, our data suggest that therapeutic strategies that enhance IGF2 signalling and adult neurogenesis might be suitable to treat disease linked to excessive fear memory. PMID:21873981

Recent developments in the behavioural and pharmacological enhancement of extinction of drug seeking.

PubMed

Chesworth, Rose; Corbit, Laura H

2017-01-01

One of the principal barriers to overcoming addiction is the propensity to relapse, even after months or years of abstinence. Relapse can be precipitated by cues and contexts associated with drug use; thus, decreasing the conditioned properties of these cues and contexts may assist in preventing relapse. The predictive power of drug cues and contexts can be reduced by repeatedly presenting them in the absence of the drug reinforcer, a process known as extinction. The potential of extinction to limit relapse has generated considerable interest and research over the past few decades. While pre-clinical animal models suggest extinction learning assists relapse prevention, treatment efficacy is often lacking when extinction learning principles are translated into clinical trials. Conklin and Tiffany (Addiction, 2002) suggest the lack of efficacy in clinical practice may be due to limited translation of procedures demonstrated through animal research and propose several methodological improvements to enhance extinction learning for drug addiction. This review will examine recent advances in the behavioural and pharmacological manipulation of extinction learning, based on research from pre-clinical models. In addition, the translation of pre-clinical findings-both those suggested by Conklin and Tiffany () and novel demonstrations from the past 13 years-into clinical trials and the efficacy of these methods in reducing craving and relapse, where available, will be discussed. Finally, we highlight areas where promising pre-clinical models have not yet been integrated into current clinical practice but, if applied, could improve upon existing behavioural and pharmacological methods. © 2015 Society for the Study of Addiction.

Learning to inhibit the response during instrumental (operant) extinction

PubMed Central

Bouton, Mark E.; Trask, Sydney; Carranza-Jasso, Rodrigo

2016-01-01

Five experiments tested implications of the idea that instrumental (operant) extinction involves learning to inhibit the learned response. All experiments used a discriminated operant procedure in which rats were reinforced for lever pressing or chain pulling in the presence of a discriminative stimulus (S), but not in its absence. In Experiment 1, extinction of the response (R) in the presence of S weakened responding in S, but equivalent nonreinforced exposure to S (without the opportunity to make R) did not. Experiment 2 replicated that result and found that extinction of R had no effect on a different R that had also been reinforced in the stimulus. In Experiments 3 and 4, rats first learned to perform several different stimulus and response combinations (S1R1, S2R1, S3R2, and S4R2). Extinction of a response in one stimulus (i.e., S1R1) transferred and weakened the same response, but not a different response, when it was tested in another stimulus (i.e., S2R1 but not S3R2). In Experiment 5, extinction still transferred between S1 and S2 when the stimuli set the occasion for R's association with different types of food pellets. The results confirm the importance of response inhibition in instrumental extinction: Nonreinforcement of the response in S causes the most effective suppression of responding, and response suppression is specific to the response but transfers and influences performance of the same response when it is occasioned by other stimuli. Theoretical and practical implications are discussed. PMID:27379715

Learning and the persistence of appetite: extinction and the motivation to eat and overeat.

PubMed

Bouton, Mark E

2011-04-18

The modern world is saturated with highly palatable and highly available food, providing many opportunities to associate food with environmental cues and actions (through Pavlovian and operant or instrumental learning, respectively). Basic learning processes can often increase the tendency to approach and consume food, whereas extinction, in which Pavlovian and operant behaviors decline when the reinforcer is withheld, weakens but does not erase those tendencies. Contemporary research suggests that extinction involves an inhibitory form of new learning that appears fragile because it is highly dependent on the context for expression. These ideas are supported by the phenomena of renewal, spontaneous recovery, resurgence, reinstatement, and rapid reacquisition in appetitive learning, which together may help explain why overeating may be difficult to suppress permanently, and why appetitive behavior may seem so persistent. Copyright © 2010. Published by Elsevier Inc.

Enhancing exposure therapy for anxiety disorders with glucocorticoids: from basic mechanisms of emotional learning to clinical applications.

PubMed

Bentz, Dorothée; Michael, Tanja; de Quervain, Dominique J-F; Wilhelm, Frank H

2010-03-01

Current neurophysiological and psychological accounts view exposure therapy as the clinical analog of extinction learning that results in persistent modifications of the fear memory involved in the pathogenesis, symptomatology, and maintenance of anxiety disorders. Evidence from studies in animals and humans indicate that glucocorticoids have the potential to facilitate the processes that underlie extinction learning during exposure therapy. Particularly, glucocorticoids can restrict retrieval of previous aversive learning episodes and enhance consolidation of memory traces relating to non-fearful responding in feared situations. Thus, glucocorticoid treatment especially in combination with exposure therapy might be a promising approach to optimize treatment of anxiety disorders. This review examines the processes involved in aversive conditioning, fear learning and fear extinction, and how glucocorticoids might enhance restructuring of fear memories during therapy. Copyright 2009 Elsevier Ltd. All rights reserved.

Forming competing fear learning and extinction memories in adolescence makes fear difficult to inhibit

PubMed Central

Richardson, Rick

2015-01-01

Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats (n = 170) were tested for extinction retention after conditioning and extinction at different ages. We examined neural correlates of impaired extinction retention by detection of phosphorylated mitogen-activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions. Unexpectedly, adolescent rats exhibited good extinction retention if fear was acquired before adolescence. Further, fear acquired in adolescence could be successfully extinguished in adulthood but not within adolescence. Adolescent rats did not show extinction-induced increases in pMAPK-IR in the medial prefrontal cortex or the basolateral amygdala, or a pattern of reduced caudal central amygdala pMAPK-IR, as was observed in juveniles. This dampened prefrontal and basolateral amygdala MAPK activation following extinction in adolescence occurred even when there was no impairment in extinction retention. In contrast, only adolescent animals that exhibited impaired extinction retention showed elevated pMAPK-IR in the posterior paraventricular thalamus. These data suggest that neither the animal's age at the time of fear acquisition or extinction determines whether impaired extinction retention is exhibited. Rather, it appears that forming competing fear conditioning and extinction memories in adolescence renders this a vulnerable developmental period in which fear is difficult to inhibit. Furthermore, even under conditions that promote good extinction, the neural correlates of extinction in adolescence are different than those recruited in animals of other ages. PMID:26472643

Role of Medial Prefrontal Cortex Narp in the Extinction of Morphine Conditioned Place Preference

ERIC Educational Resources Information Center

Blouin, Ashley M.; Han, Sungho; Pearce, Anne M.; Cheng, KaiLun; Lee, JongAh J.; Johnson, Alexander W.; Wang, Chuansong; During, Matthew J.; Holland, Peter C.; Shaham, Yavin; Baraban, Jay M.; Reti, Irving M.

2013-01-01

Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus…

Extinction of Chained Instrumental Behaviors: Effects of Procurement Extinction on Consumption Responding

PubMed Central

Thrailkill, Eric A.; Bouton, Mark E.

2015-01-01

Instrumental behavior often consists of sequences or chains of responses that minimally include procurement behaviors that enable subsequent consumption behaviors. In such chains, behavioral units are linked by access to one another and eventually to a primary reinforcer, such as food or a drug. The present experiments examined the effects of extinguishing procurement responding on consumption responding after training of a discriminated heterogeneous instrumental chain. Rats learned to make a procurement response (e.g., pressing a lever) in the presence of a distinctive discriminative stimulus; making that response led to the presentation of a second discriminative stimulus that set the occasion for a consumption response (e.g., pulling a chain), which then produced a food-pellet reinforcer. Experiment 1 showed that extinction of either the full procurement-consumption chain or procurement alone weakened the consumption response tested in isolation. Experiment 2 replicated the procurement extinction effect and further demonstrated that the opportunity to make the procurement response, as opposed to simple exposure to the procurement stimulus alone, was required. In Experiment 3, rats learned 2 distinct discriminated heterogeneous chains; extinction of 1 procurement response specifically weakened the consumption response that had been associated with it. The results suggest that learning to inhibit the procurement response may produce extinction of consumption responding through mediated extinction. The experiments suggest the importance of an associative analysis of instrumental behavior chains. PMID:25915751

Neural correlates of two different types of extinction learning in the amygdala central nucleus.

PubMed

Iordanova, Mihaela D; Deroche, Mickael L D; Esber, Guillem R; Schoenbaum, Geoffrey

2016-08-17

Extinction is a fundamental form of memory updating in which one learns to stop expecting an event that no longer occurs. This learning ensues when one experiences a change in environmental contingencies, that is, when an expected outcome fails to occur (simple extinction), or when a novel inflated expectation of a double outcome (overexpectation) is in conflict with the real outcome, and is a process that has been linked to amygdala function. Here, we show that in rats, the same neuronal population in the amygdala central nucleus updates reward expectancies and behaviour in both types of extinction, and neural changes in one paradigm are reflected in the other. This work may have implications for the management of addiction and anxiety disorders that require treatments based on the outcome omission, and disorders such as obesity that could use overexpectation, but not omission strategies.

Opposite effects of fear conditioning and extinction on dendritic spine remodelling.

PubMed

Lai, Cora Sau Wan; Franke, Thomas F; Gan, Wen-Biao

2012-02-19

It is generally believed that fear extinction is a form of new learning that inhibits rather than erases previously acquired fear memories. Although this view has gained much support from behavioural and electrophysiological studies, the hypothesis that extinction causes the partial erasure of fear memories remains viable. Using transcranial two-photon microscopy, we investigated how neural circuits are modified by fear learning and extinction by examining the formation and elimination of postsynaptic dendritic spines of layer-V pyramidal neurons in the mouse frontal association cortex. Here we show that fear conditioning by pairing an auditory cue with a footshock increases the rate of spine elimination. By contrast, fear extinction by repeated presentation of the same auditory cue without a footshock increases the rate of spine formation. The degrees of spine remodelling induced by fear conditioning and extinction strongly correlate with the expression and extinction of conditioned fear responses, respectively. Notably, spine elimination and formation induced by fear conditioning and extinction occur on the same dendritic branches in a cue- and location-specific manner: cue-specific extinction causes formation of dendritic spines within a distance of two micrometres from spines that were eliminated after fear conditioning. Furthermore, reconditioning preferentially induces elimination of dendritic spines that were formed after extinction. Thus, within vastly complex neuronal networks, fear conditioning, extinction and reconditioning lead to opposing changes at the level of individual synapses. These findings also suggest that fear memory traces are partially erased after extinction.

Administration of riluzole to the basolateral amygdala facilitates fear extinction in rats.

PubMed

Sugiyama, Azusa; Yamada, Misa; Saitoh, Akiyoshi; Oka, Jun-Ichiro; Yamada, Mitsuhiko

2018-01-15

A general understanding exists that inhibition of glutamatergic neurotransmission in the basolateral amygdala (BLA) impairs fear extinction in rodents. Surprisingly, we recently found that systemic administration of riluzole, which has been shown to inhibit the glutamatergic system, facilitates extinction learning in rats with a preconditioned contextual fear response. However, the mechanisms underlying this paradoxical effect of riluzole remain unclear. In this study, adult male Wistar rats were bilaterally cannulated in the BLA to examine the effects of intra-BLA administration of riluzole. We also compared the effects of riluzole with those of d-cycloserine, a partial agonist at the glycine-binding region of the N-methyl-d-aspartate (NMDA) receptor. In this study, intra-BLA administration of either riluzole or d-cycloserine facilitated extinction learning of contextual fear in conditioned rats. In addition, both riluzole and d-cycloserine enhanced the acquisition of recognition memory in the same model. However, intra-BLA injections of riluzole, but not d-cycloserine, had a potent anxiolytic-like effect when investigated using an elevated plus-maze test. Our findings suggest that riluzole-induced facilitation of extinction learning in rats with a preconditioned contextual fear reflects an indirect effect, resulting from the intra-BLA administration of the drug, and might not be directly related to inhibition of glutamatergic signaling. Further research is needed to clarify the mechanisms underlying the paradoxical effect of riluzole on fear extinction learning observed in this study. Copyright © 2017 Elsevier B.V. All rights reserved.

The effect of ketamine on the consolidation and extinction of contextual fear memory

PubMed Central

Thomas, Kerrie L; Hall, Jeremy

2018-01-01

Ketamine, principally an antagonist of N-methyl-ᴅ-aspartate receptors, induces schizophrenia-like symptoms in adult humans, warranting its use in the investigation of psychosis-related phenotypes in animal models. Genomic studies further implicate N-methyl-ᴅ-aspartate receptor-mediated processes in schizophrenia pathology, together with more broadly-defined synaptic plasticity and associative learning processes. Strong pathophysiological links have been demonstrated between fear learning and psychiatric disorders such as schizophrenia. To further investigate the impact of ketamine on associative fear learning, we studied the effects of pre- and post-training ketamine on the consolidation and extinction of contextual fear memory in rats. Administration of 25 mg/kg ketamine prior to fear conditioning did not affect consolidation when potentially confounding effects of state dependency were controlled for. Pre-training ketamine (25 mg/kg) impaired the extinction of the conditioned fear response, which was mirrored with the use of a lower dose (8 mg/kg). Post-training ketamine (25 mg/kg) had no effect on the consolidation or extinction of conditioned fear. These observations implicate processes relating to the extinction of contextual fear memory in the manifestation of ketamine-induced phenotypes, and are consistent with existing hypotheses surrounding abnormal associative learning in schizophrenia. PMID:29338491

Disrupting nNOS-PSD-95 coupling in the hippocampal dentate gyrus promotes extinction memory retrieval.

PubMed

Li, Jun; Han, Zhou; Cao, Bo; Cai, Cheng-Yun; Lin, Yu-Hui; Li, Fei; Wu, Hai-Ying; Chang, Lei; Luo, Chun-Xia; Zhu, Dong-Ya

2017-11-04

Granule cells in the dentate gyrus regenerate constantly in adult hippocampus and then integrate into neural circuits in the hippocampus thereby providing the neural basis for learning and memory. Promoting the neurogenesis in the hippocampus facilitates learning and memory such as spatial learning, object identification, and extinction learning. The interaction between neuronal nitric oxide synthase (nNOS) and postsynaptic density protein-95 (PSD-95) is reported to negatively regulate neurogenesis in brain, so we hypothesized that disrupting this interaction might facilitate the neurogenesis in the dentate gyrus (DG) and thus enhance the extinction memory retrieval of fear learning. We found that uncoupling the nNOS-PSD-95 complex in remote contextual fear condition promoted both neuronal proliferation and survival in the DG, contributing to an enhanced retrieval of the extinction memory. Moreover, the nNOS-PSD-95 uncoupling-induced neurogenesis may be mediated by the extracellular signal-regulated kinase (ERK) as the phosphorylation level of ERK1/2 was increased after uncoupling. These findings suggest that the nNOS-PSD-95 complex may serve as a novel target for the treatment of post-traumatic stress disorder (PTSD). Copyright © 2017 Elsevier Inc. All rights reserved.

Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder

PubMed Central

Milad, Mohammed R.; Pitman, Roger K.; Ellis, Cameron B.; Gold, Andrea L.; Shin, Lisa M; Lasko, Natasha B.; Zeidan, Mohamed A.; Handwerger, Kathryn; Orr, Scott P.; Rauch, Scott L.

2009-01-01

Background: A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC). Methods: Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD controls (TENCs) underwent a two-day fear conditioning and extinction protocol in a 3T fMRI scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response. Results: SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of fMRI data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC, and greater activation in dACC, was observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing. Conclusions: These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment. PMID:19748076

Modulation of 7 T fMRI Signal in the Cerebellar Cortex and Nuclei During Acquisition, Extinction, and Reacquisition of Conditioned Eyeblink Responses.

PubMed

Ernst, Thomas M; Thürling, Markus; Müller, Sarah; Kahl, Fabian; Maderwald, Stefan; Schlamann, Marc; Boele, Henk-Jan; Koekkoek, Sebastiaan K E; Diedrichsen, Jörn; De Zeeuw, Chris I; Ladd, Mark E; Timmann, Dagmar

2017-08-01

Classical delay eyeblink conditioning is likely the most commonly used paradigm to study cerebellar learning. As yet, few studies have focused on extinction and savings of conditioned eyeblink responses (CRs). Saving effects, which are reflected in a reacquisition after extinction that is faster than the initial acquisition, suggest that learned associations are at least partly preserved during extinction. In this study, we tested the hypothesis that acquisition-related plasticity is nihilated during extinction in the cerebellar cortex, but retained in the cerebellar nuclei, allowing for faster reacquisition. Changes of 7 T functional magnetic resonance imaging (fMRI) signals were investigated in the cerebellar cortex and nuclei of young and healthy human subjects. Main effects of acquisition, extinction, and reacquisition against rest were calculated in conditioned stimulus-only trials. First-level β values were determined for a spherical region of interest (ROI) around the acquisition peak voxel in lobule VI, and dentate and interposed nuclei ipsilateral to the unconditioned stimulus. In the cerebellar cortex and nuclei, fMRI signals were significantly lower in extinction compared to acquisition and reacquisition, but not significantly different between acquisition and reacquisition. These findings are consistent with the theory of bidirectional learning in both the cerebellar cortex and nuclei. It cannot explain, however, why conditioned responses reappear almost immediately in reacquisition following extinction. Although the present data do not exclude that part of the initial memory remains in the cerebellum in extinction, future studies should also explore changes in extracerebellar regions as a potential substrate of saving effects. Hum Brain Mapp 38:3957-3974, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Enduring abolishment of remote but not recent expression of conditioned fear by the blockade of calcium-permeable AMPA receptors before extinction training.

PubMed

Zelena, Dóra; Mikics, Éva; Balázsfi, Diána; Varga, János; Klausz, Barbara; Urbán, Eszter; Sipos, Eszter; Biró, László; Miskolczi, Christina; Kovács, Krisztina; Ferenczi, Szilamér; Haller, József

2016-06-01

Calcium-permeable (GluA2 subunit-free) AMPA receptors (CP-AMPAR) play prominent roles in fear extinction; however, no blockers of these receptors were studied in tests relevant to extinction learning so far. The CP-AMPAR antagonist IEM-1460 was administered once before extinction trainings, which were started either 1 or 28 days after fear conditioning (FC). We used a mild extinction protocol that durably decreased but did not abolish conditioned fear. The messenger RNA (mRNA) expression of GluA1 and GluA2 subunits were investigated at both time points in the ventromedial prefrontal cortex (vmPFC) and amygdala. IEM-1460 transiently facilitated extinction 1 day after conditioning, but learned fear spontaneously recovered 4 weeks later. When the extinction protocol was applied 28 days after training, IEM-1460 enhanced extinction memory, moreover abolished conditioned fear for at least a month. The expression of GluA1 and GluA2 mRNAs was increased at both time points in the vmPFC. In the basolateral and central amygdala, the GluA1/GluA2 mRNA ratio increased, suggesting a shift towards the preponderance of GluA1 over GluA2 expression. AMPAR blockade lastingly enhanced the extinction of remote but not recent fear memories. Time-dependent changes in AMPA receptor subunit mRNA expression may explain the differential effects of CP-AMPAR blockade on recent and remote conditioned fear, further supporting the notion that the mechanisms maintaining learned fear change over time. Our findings suggest clinical implications for CP-AMPAR blockers, particularly for acquired anxieties (e.g., post-traumatic stress disorder) which have a slow onset and are durable.

Therapeutic Effects of Extinction Learning as a Model of Exposure Therapy in Rats.

PubMed

Fucich, Elizabeth A; Paredes, Denisse; Morilak, David A

2016-12-01

Current treatments for stress-related psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), are inadequate. Cognitive behavioral psychotherapies, including exposure therapy, are an alternative to pharmacotherapy, but the neurobiological mechanisms are unknown. Preclinical models demonstrating therapeutic effects of behavioral interventions are required to investigate such mechanisms. Exposure therapy bears similarity to extinction learning. Thus, we investigated the therapeutic effects of extinction learning as a behavioral intervention to model exposure therapy in rats, testing its effectiveness in reversing chronic stress-induced deficits in cognitive flexibility and coping behavior that resemble dimensions of depression and PTSD. Rats were fear-conditioned by pairing a tone with footshock, and then exposed to chronic unpredictable stress (CUS) that induces deficits in cognitive set-shifting and active coping behavior. They then received an extinction learning session as a therapeutic intervention by repeated exposure to the tone with no shock. Effects on cognitive flexibility and coping behavior were assessed 24 h later on the attentional set-shifting test or shock-probe defensive burying test, respectively. Extinction reversed the CUS-induced deficits in cognitive flexibility and coping behavior, and increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex (mPFC) of stress-compromised rats, suggesting a role for activity-dependent protein synthesis in the therapeutic effect. Inhibiting protein synthesis by microinjecting anisomycin into mPFC blocked the therapeutic effect of extinction on cognitive flexibility. These results demonstrate the utility of extinction as a model by which to study mechanisms underlying exposure therapy, and suggest these mechanisms involve protein synthesis in the mPFC, the further study of which may identify novel therapeutic targets.

Therapeutic Effects of Extinction Learning as a Model of Exposure Therapy in Rats

PubMed Central

Fucich, Elizabeth A; Paredes, Denisse; Morilak, David A

2016-01-01

Current treatments for stress-related psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), are inadequate. Cognitive behavioral psychotherapies, including exposure therapy, are an alternative to pharmacotherapy, but the neurobiological mechanisms are unknown. Preclinical models demonstrating therapeutic effects of behavioral interventions are required to investigate such mechanisms. Exposure therapy bears similarity to extinction learning. Thus, we investigated the therapeutic effects of extinction learning as a behavioral intervention to model exposure therapy in rats, testing its effectiveness in reversing chronic stress-induced deficits in cognitive flexibility and coping behavior that resemble dimensions of depression and PTSD. Rats were fear-conditioned by pairing a tone with footshock, and then exposed to chronic unpredictable stress (CUS) that induces deficits in cognitive set-shifting and active coping behavior. They then received an extinction learning session as a therapeutic intervention by repeated exposure to the tone with no shock. Effects on cognitive flexibility and coping behavior were assessed 24 h later on the attentional set-shifting test or shock-probe defensive burying test, respectively. Extinction reversed the CUS-induced deficits in cognitive flexibility and coping behavior, and increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex (mPFC) of stress-compromised rats, suggesting a role for activity-dependent protein synthesis in the therapeutic effect. Inhibiting protein synthesis by microinjecting anisomycin into mPFC blocked the therapeutic effect of extinction on cognitive flexibility. These results demonstrate the utility of extinction as a model by which to study mechanisms underlying exposure therapy, and suggest these mechanisms involve protein synthesis in the mPFC, the further study of which may identify novel therapeutic targets. PMID:27417516

Learning to inhibit the response during instrumental (operant) extinction.

PubMed

Bouton, Mark E; Trask, Sydney; Carranza-Jasso, Rodrigo

2016-07-01

Five experiments tested implications of the idea that instrumental (operant) extinction involves learning to inhibit the learned response. All experiments used a discriminated operant procedure in which rats were reinforced for lever pressing or chain pulling in the presence of a discriminative stimulus (S), but not in its absence. In Experiment 1, extinction of the response (R) in the presence of S weakened responding in S, but equivalent nonreinforced exposure to S (without the opportunity to make R) did not. Experiment 2 replicated that result and found that extinction of R had no effect on a different R that had also been reinforced in the stimulus. In Experiments 3 and 4, rats first learned to perform several different stimulus and response combinations (S1R1, S2R1, S3R2, and S4R2). Extinction of a response in one stimulus (i.e., S1R1) transferred and weakened the same response, but not a different response, when it was tested in another stimulus (i.e., S2R1 but not S3R2). In Experiment 5, extinction still transferred between S1 and S2 when the stimuli set the occasion for R's association with different types of food pellets. The results confirm the importance of response inhibition in instrumental extinction: Nonreinforcement of the response in S causes the most effective suppression of responding, and response suppression is specific to the response but transfers and influences performance of the same response when it is occasioned by other stimuli. Theoretical and practical implications are discussed. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Contextual-Specificity of Short-Delay Extinction in Humans: Renewal of Fear-Potentiated Startle in a Virtual Environment

ERIC Educational Resources Information Center

Alvarez, Ruben P.; Johnson, Linda; Grillon, Christian

2007-01-01

A recent fear-potentiated startle study in rodents suggested that extinction was not context dependent when extinction was conducted after a short delay following acquisition, suggesting that extinction can lead to erasure of fear learning in some circumstances. The main objective of this study was to attempt to replicate these findings in humans…

All about Endangered and Extinct Animals. Animal Life for Children. [Videotape].

ERIC Educational Resources Information Center

2000

While there are thousands of different animals in the world, some have been extinct for many years and others are on the verge of extinction. In this videotape, students learn about the natural and man-made factors that lead to the endangerment and extinction of animals. Children find out why it is essential for people to help all forms of…

Medial prefrontal cortex activity during the extinction of conditioned fear: an investigation using functional near-infrared spectroscopy.

PubMed

Guhn, Anne; Dresler, Thomas; Hahn, Tim; Mühlberger, Andreas; Ströhle, Andreas; Deckert, Jürgen; Herrmann, Martin J

2012-06-01

The majority of fear conditioning studies in humans have focused on fear acquisition rather than fear extinction. For this reason only a few functional imaging studies on fear extinction are available. A large number of animal studies indicate the medial prefrontal cortex (mPFC) as neuronal substrate of extinction. We therefore determined mPFC contribution during extinction learning after a discriminative fear conditioning in 34 healthy human subjects by using functional near-infrared spectroscopy. During the extinction training, a previously conditioned neutral face (conditioned stimulus, CS+) no longer predicted an aversive scream (unconditioned stimulus, UCS). Considering differential valence and arousal ratings as well as skin conductance responses during the acquisition phase, we found a CS+ related increase in oxygenated haemoglobin concentration changes within the mPFC over the time course of extinction. Late CS+ trials further revealed higher activation than CS- trials in a cluster of probe set channels covering the mPFC. These results are in line with previous findings on extinction and further emphasize the mPFC as significant for associative learning processes. During extinction, the diminished fear association between a former CS+ and a UCS is inversely correlated with mPFC activity--a process presumably dysfunctional in anxiety disorders. Copyright © 2012 S. Karger AG, Basel.

Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning.

PubMed

Xu, Jian; Zhu, Yongling; Kraniotis, Stephen; He, Qionger; Marshall, John J; Nomura, Toshihiro; Stauffer, Shaun R; Lindsley, Craig W; Conn, P Jeffrey; Contractor, Anis

2013-07-18

Metabotropic glutamate receptor 5 (mGluR5) plays important roles in modulating neural activity and plasticity and has been associated with several neuropathological disorders. Previous work has shown that genetic ablation or pharmacological inhibition of mGluR5 disrupts fear extinction and spatial reversal learning, suggesting that mGluR5 signaling is required for different forms of adaptive learning. Here, we tested whether ADX47273, a selective positive allosteric modulator (PAM) of mGluR5, can enhance adaptive learning in mice. We found that systemic administration of the ADX47273 enhanced reversal learning in the Morris Water Maze, an adaptive task. In addition, we found that ADX47273 had no effect on single-session and multi-session extinction, but administration of ADX47273 after a single retrieval trial enhanced subsequent fear extinction learning. Together these results demonstrate a role for mGluR5 signaling in adaptive learning, and suggest that mGluR5 PAMs represent a viable strategy for treatment of maladaptive learning and for improving behavioral flexibility.

Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning

PubMed Central

Xu, Jian; Zhu, Yongling; Kraniotis, Stephen; He, Qionger; Marshall, John J.; Nomura, Toshihiro; Stauffer, Shaun R.; Lindsley, Craig W.; Conn, P. Jeffrey; Contractor, Anis

2013-01-01

Metabotropic glutamate receptor 5 (mGluR5) plays important roles in modulating neural activity and plasticity and has been associated with several neuropathological disorders. Previous work has shown that genetic ablation or pharmacological inhibition of mGluR5 disrupts fear extinction and spatial reversal learning, suggesting that mGluR5 signaling is required for different forms of adaptive learning. Here, we tested whether ADX47273, a selective positive allosteric modulator (PAM) of mGluR5, can enhance adaptive learning in mice. We found that systemic administration of the ADX47273 enhanced reversal learning in the Morris Water Maze, an adaptive task. In addition, we found that ADX47273 had no effect on single-session and multi-session extinction, but administration of ADX47273 after a single retrieval trial enhanced subsequent fear extinction learning. Together these results demonstrate a role for mGluR5 signaling in adaptive learning, and suggest that mGluR5 PAMs represent a viable strategy for treatment of maladaptive learning and for improving behavioral flexibility. PMID:23869026

Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy

PubMed Central

2013-01-01

Background Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. While there is growing evidence that fear extinction is influenced by certain procedural variables, it is unclear how these influences might vary across individuals and subpopulations. To model individual differences in fear extinction, prior studies identified a strain of inbred mouse, 129S1/SvImJ (S1), which exhibits a profound deficit in fear extinction, as compared to other inbred strains, such as C57BL/6J (B6). Methods Here, we assessed the effects of procedural variables on the impaired extinction phenotype of the S1 strain and, by comparison, the extinction-intact B6 strain. The variables studied were 1) the interval between conditioning and extinction, 2) the interval between cues during extinction training, 3) single-cue exposure before extinction training, and 4) extinction of a second-order conditioned cue. Results Conducting extinction training soon after (‘immediately’) conditioning attenuated fear retrieval in S1 mice and impaired extinction in B6 mice. Spacing cue presentations with long inter-trial intervals during extinction training augmented fear in S1 and B6 mice. The effect of spacing was lost with one-trial fear conditioning in B6, but not S1 mice. A single exposure to a conditioned cue before extinction training did not alter extinction retrieval, either in B6 or S1 mice. Both the S1 and B6 strains exhibited robust second-order fear conditioning, in which a cue associated with footshock was sufficient to serve as a conditioned exciter to condition a fear association to a second cue. B6 mice extinguished the fear response to the second-order conditioned cue, but S1 mice failed to do so. Conclusions These data provide further evidence that fear extinction is strongly influenced by multiple procedural variables and is so in a highly strain-dependent manner. This suggests that the efficacy of extinction-based behavioral interventions, such as exposure therapy, for trauma-related anxiety disorders will be determined by the procedural parameters employed and the degree to which the patient can extinguish. PMID:23830244

The centrality of fear extinction in linking risk factors to PTSD: A narrative review.

PubMed

Zuj, Daniel V; Palmer, Matthew A; Lommen, Miriam J J; Felmingham, Kim L

2016-10-01

Recent prospective studies in emergency services have identified impaired fear extinction learning and memory to be a significant predictor of Posttraumatic Stress Disorder (PTSD), complementing a wealth of cross-sectional evidence of extinction deficits associated with the disorder. Additional fields of research show specific risk factors and biomarkers of the disorder, including candidate genotypes, stress and sex hormones, cognitive factors, and sleep disturbances. Studies in mostly nonclinical populations also reveal that the aforementioned factors are involved in fear extinction learning and memory. Here, we provide a comprehensive narrative review of the literature linking PTSD to these risk factors, and linking these risk factors to impaired fear extinction. On balance, the evidence suggests that fear extinction may play a role in the relationship between risk factors and PTSD. Should this notion hold true, this review carries important implications for the improvement of exposure-based treatments, as well as strategies for the implementation of treatment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multiple sites of extinction for a single learned response

PubMed Central

Mauk, Michael D.

2012-01-01

Most learned responses can be diminished by extinction, a process that can be engaged when a conditioned stimulus (CS) is presented but not reinforced. We present evidence that plasticity in at least two brain regions can mediate extinction of responses produced by trace eyelid conditioning, where the CS and the reinforcing stimulus are separated by a stimulus-free interval. We observed individual differences in the effects of blocking extinction mechanisms in the cerebellum, the structure that, along with several forebrain structures, mediates acquisition of trace eyelid responses; in some rabbits extinction was prevented, whereas in others it was largely unaffected. We also show that cerebellar mechanisms can mediate extinction when noncerebellar mechanisms are bypassed. Together, these observations indicate that trace eyelid responses can be extinguished via processes operating at more than one site, one in the cerebellum and one upstream in forebrain. The relative contributions of these sites may vary from animal to animal and situation to situation. PMID:21940608

The Class I HDAC Inhibitor RGFP963 Enhances Consolidation of Cued Fear Extinction

ERIC Educational Resources Information Center

Bowers, Mallory E.; Xia, Bing; Carreiro, Samantha; Ressler, Kerry J.

2015-01-01

Evidence indicates that broad, nonspecific histone deacetylase (HDAC) inhibition enhances learning and memory, however, the contribution of the various HDACs to specific forms of learning is incompletely understood. Here, we show that the Class I HDAC inhibitor, RGFP963, enhances consolidation of cued fear extinction. However, RGFP966, a strong…

Contingency Awareness Shapes Acquisition and Extinction of Emotional Responses in a Conditioning Model of Pain-Related Fear

PubMed Central

Labrenz, Franziska; Icenhour, Adriane; Benson, Sven; Elsenbruch, Sigrid

2015-01-01

As a fundamental learning process, fear conditioning promotes the formation of associations between predictive cues and biologically significant signals. In its application to pain, conditioning may provide important insight into mechanisms underlying pain-related fear, although knowledge especially in interoceptive pain paradigms remains scarce. Furthermore, while the influence of contingency awareness on excitatory learning is subject of ongoing debate, its role in pain-related acquisition is poorly understood and essentially unknown regarding extinction as inhibitory learning. Therefore, we addressed the impact of contingency awareness on learned emotional responses to pain- and safety-predictive cues in a combined dataset of two pain-related conditioning studies. In total, 75 healthy participants underwent differential fear acquisition, during which rectal distensions as interoceptive unconditioned stimuli (US) were repeatedly paired with a predictive visual cue (conditioned stimulus; CS+) while another cue (CS−) was presented unpaired. During extinction, both CS were presented without US. CS valence, indicating learned emotional responses, and CS-US contingencies were assessed on visual analog scales (VAS). Based on an integrative measure of contingency accuracy, a median-split was performed to compare groups with low vs. high contingency accuracy regarding learned emotional responses. To investigate predictive value of contingency accuracy, regression analyses were conducted. Highly accurate individuals revealed more pronounced negative emotional responses to CS+ and increased positive responses to CS− when compared to participants with low contingency accuracy. Following extinction, highly accurate individuals had fully extinguished pain-predictive cue properties, while exhibiting persistent positive emotional responses to safety signals. In contrast, individuals with low accuracy revealed equally positive emotional responses to both, CS+ and CS−. Contingency accuracy predicted variance in the formation of positive responses to safety cues while no predictive value was found for danger cues following acquisition and for neither cue following extinction. Our findings underscore specific roles of learned danger and safety in pain-related acquisition and extinction. Contingency accuracy appears to distinctly impact learned emotional responses to safety and danger cues, supporting aversive learning to occur independently from CS-US awareness. The interplay of cognitive and emotional factors in shaping excitatory and inhibitory pain-related learning may contribute to altered pain processing, underscoring its clinical relevance in chronic pain. PMID:26640433

Contingency Awareness Shapes Acquisition and Extinction of Emotional Responses in a Conditioning Model of Pain-Related Fear.

PubMed

Labrenz, Franziska; Icenhour, Adriane; Benson, Sven; Elsenbruch, Sigrid

2015-01-01

As a fundamental learning process, fear conditioning promotes the formation of associations between predictive cues and biologically significant signals. In its application to pain, conditioning may provide important insight into mechanisms underlying pain-related fear, although knowledge especially in interoceptive pain paradigms remains scarce. Furthermore, while the influence of contingency awareness on excitatory learning is subject of ongoing debate, its role in pain-related acquisition is poorly understood and essentially unknown regarding extinction as inhibitory learning. Therefore, we addressed the impact of contingency awareness on learned emotional responses to pain- and safety-predictive cues in a combined dataset of two pain-related conditioning studies. In total, 75 healthy participants underwent differential fear acquisition, during which rectal distensions as interoceptive unconditioned stimuli (US) were repeatedly paired with a predictive visual cue (conditioned stimulus; CS(+)) while another cue (CS(-)) was presented unpaired. During extinction, both CS were presented without US. CS valence, indicating learned emotional responses, and CS-US contingencies were assessed on visual analog scales (VAS). Based on an integrative measure of contingency accuracy, a median-split was performed to compare groups with low vs. high contingency accuracy regarding learned emotional responses. To investigate predictive value of contingency accuracy, regression analyses were conducted. Highly accurate individuals revealed more pronounced negative emotional responses to CS(+) and increased positive responses to CS(-) when compared to participants with low contingency accuracy. Following extinction, highly accurate individuals had fully extinguished pain-predictive cue properties, while exhibiting persistent positive emotional responses to safety signals. In contrast, individuals with low accuracy revealed equally positive emotional responses to both, CS(+) and CS(-). Contingency accuracy predicted variance in the formation of positive responses to safety cues while no predictive value was found for danger cues following acquisition and for neither cue following extinction. Our findings underscore specific roles of learned danger and safety in pain-related acquisition and extinction. Contingency accuracy appears to distinctly impact learned emotional responses to safety and danger cues, supporting aversive learning to occur independently from CS-US awareness. The interplay of cognitive and emotional factors in shaping excitatory and inhibitory pain-related learning may contribute to altered pain processing, underscoring its clinical relevance in chronic pain.

D-cycloserine enhances generalization of fear extinction in children.

PubMed

Byrne, Simon P; Rapee, Ronald M; Richardson, Rick; Malhi, Gin S; Jones, Michael; Hudson, Jennifer L

2015-06-01

For exposure therapy to be successful, it is essential that fear extinction learning extends beyond the treatment setting. D-cycloserine (DCS) may facilitate treatment gains by increasing generalization of extinction learning, however, its effects have not been tested in children. We examined whether DCS enhanced generalization of fear extinction learning across different stimuli and contexts among children with specific phobias. The study was a double-blind placebo-controlled randomized controlled trial among dog or spider phobic children aged 6-14. Participants ingested either 50 mg of DCS (n = 18) or placebo (n = 17) before receiving a single prolonged exposure session to their feared stimulus. Return of fear was examined 1 week later to a different stimulus (a different dog or spider), presented in both the original treatment context and an alternate context. Avoidance and fear were measured with Behavior Approach Tests (BATs), where the child was asked to increase proximity to the stimulus while reporting their fear level. There were no differences in BAT performance between groups during the exposure session or when a new stimulus was later presented in the treatment context. However, when the new stimulus was presented in a different context, relative to placebo, the DCS group showed less avoidance (P = .03) and less increase in fear (P = .04) with moderate effect sizes. DCS enabled children to better retain their fear extinction learning. This new learning generalized to different stimuli and contexts. © 2015 Wiley Periodicals, Inc.

Adrenergic Transmission Facilitates Extinction of Conditional Fear in Mice

ERIC Educational Resources Information Center

Barad, Mark; Cain, Christopher K.; Blouin, Ashley M.

2004-01-01

Extinction of classically conditioned fear, like its acquisition, is active learning, but little is known about its molecular mechanisms. We recently reported that temporal massing of conditional stimulus (CS) presentations improves extinction memory acquisition, and suggested that temporal spacing was less effective because individual CS…

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction.

PubMed

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-12-06

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory.

The effects of extinction-aroused attention on context conditioning.

PubMed

Nelson, James Byron; Fabiano, Andrew M; Lamoureux, Jeffrey A

2018-04-01

Two experiments assessed the effects of extinguishing a conditioned cue on subsequent context conditioning. Each experiment used a different video-game method where sensors predicted attacking spaceships and participants responded to the sensor in a way that prepared them for the upcoming attack. In Experiment 1 extinction of a cue which signaled a spaceship-attack outcome facilitated subsequent learning when the attack occurred unsignaled. In Experiment 2 extinction of a cue facilitated subsequent learning, regardless of whether the spaceship outcome was the same or different as used in the earlier training. In neither experiment did the extinction context become inhibitory. Results are discussed in terms of current associative theories of attention and conditioning. © 2018 Nelson et al.; Published by Cold Spring Harbor Laboratory Press.

Expanding the Intertrial Interval During Extinction: Response Cessation and Recovery

PubMed Central

Orinstein, Alyssa J.; Urcelay, Gonzalo P.; Miller, Ralph R.

2010-01-01

We examined trial spacing during extinction following a human contingency learning task. Specifically, we assessed if an expanding retrieval practice schedule (Bjork & Bjork, 1992, 2006), in which the spacing between extinction trials was progressively increased, would result in faster immediate extinction and less recovery from extinction than uniformly spaced extinction trials. We used an ABB vs. ABA renewal design and observed that, whereas the expanding group extinguished faster during extinction treatment, the expanding and constant groups showed the same level of extinction with an immediate test in the extinction context (ABB) and the two groups showed equivalent ABA renewal at test in the training context. We conclude that the faster extinction observed in the expanding groups could be misleading in clinical treatment, if the therapist used the absence of fear during extinction as the basis for terminating treatment. PMID:20171324

Extinction, Reacquisition, and Rapid Forgetting of Eyeblink Conditioning in Developing Rats

ERIC Educational Resources Information Center

Brown, Kevin L.; Freeman, John H.

2014-01-01

Eyeblink conditioning is a well-established model for studying the developmental neurobiology of associative learning and memory. However, age differences in extinction and subsequent reacquisition have yet to be studied using this model. The present study examined extinction and reacquisition of eyeblink conditioning in developing rats. In…

The Effects of Partial Reinforcement in the Acquisition and Extinction of Recurrent Serial Patterns.

ERIC Educational Resources Information Center

Dockstader, Steven L.

The purpose of these 2 experiments was to determine whether sequential response pattern behavior is affected by partial reinforcement in the same way as other behavior systems. The first experiment investigated the partial reinforcement extinction effects (PREE) in a sequential concept learning task where subjects were required to learn a…

Individual Differences in the Severely Retarded Child in Acquisition, Stimulus Generalization, and Extinction in Go-No-Go Discrimination Learning

ERIC Educational Resources Information Center

Evans, P. L. C.; Hogg, J. H.

1975-01-01

This study relates excitatory and inhibitory personality variables of a heterogeneous group of severely retarded children to performance on a discrete trial, successive go-no-go intradimensional discrimination learning problem, which was followed by stimulus generalization tests on a color hue continuum and extinction trials. (GO)

Facilitation of extinction of operant behaviour in C57Bl/6 mice by chlordiazepoxide and D-cycloserine.

PubMed

Leslie, Julian C; Norwood, Kelly; Kennedy, Paul J; Begley, Michael; Shaw, David

2012-09-01

Effects on the extinction of GABAergic drug, chlordiazepoxide (CDP), and glutamatergic drug, D: -cycloserine (DCS), in C57BL/6 mice were compared. Following a palatability test (Experiment 1), Experiments 2-6 involved food-reinforced lever press training followed by extinction sessions at 1- or 4-day intervals. The effects of drugs were examined. Experiment 7 involved a two-lever task. CDP did not affect food palatability (Experiment 1), but facilitated extinction when administered prior to extinction sessions via intracerebral (Experiment 2) or peripheral administration at 1-day (Experiments 3-7) or 4-day intervals (Experiment 6). Reducing the amount of training prior to extinction reduced the delay in the effect of CDP typically seen, and CDP had a larger effect in early sessions on mice that had received less training (Experiment 3). There was some evidence that CDP could be blocked by flumazenil (Experiment 4), and CDP withdrawal reversed extinction facilitation (Experiments 5 and 7). With 4-day intervals, DCS administered immediately following extinction sessions, or pre-session CDP, facilitated extinction with 48-trial sessions (experiment 6B). With six-trial sessions, the co-administration of post-session DCS enhanced facilitation produced by pre-session CDP (experiment 6A). Finally, CDP facilitated extinction in a dose-related fashion following training on a two-lever food-reinforced task (Experiment 7). The findings are consistent with the hypotheses that two neurotransmitter systems have different roles in operant extinction and that glutamatergic systems are involved in extinction learning and GABAergic systems involved in the expression of that learning. This parallels findings with extinction following Pavlovian conditioning, which has been more extensively investigated.

Lack of renewal effect in extinction of naturally acquired conditioned eyeblink responses, but possible dependency on physical context.

PubMed

Claassen, J; Mazilescu, L; Thieme, A; Bracha, V; Timmann, D

2016-01-01

Context dependency of extinction is well known and has extensively been studied in fear conditioning, but has rarely been assessed in eyeblink conditioning. One way to demonstrate context dependency of extinction is the renewal effect. ABA paradigms are most commonly used to show the renewal effect of extinguished learned fear: if acquisition takes place in context A, and extinction takes place in context B (extinction phase), learned responses will recover in subsequent extinction trials presented in context A (renewal phase). The renewal effect of the visual threat eyeblink response (VTER), a conditioned eyeblink response, which is naturally acquired in early infancy, was examined in a total of 48 young and healthy participants with two experiments using an ABA paradigm. Twenty paired trials were performed in context A (baseline trials), followed by 50 extinction trials in context B (extinction phase) and 50 extinction trials in context A (renewal phase). In 24 participants, contexts A and B were two different rooms, and in the other 24 participants, two different background colors (orange and blue) and noises were used. To rule out spontaneous recovery, an AAA design was used for comparison. There were significant effects of extinction in both experiments. No significant renewal effects were observed. In experiment 2, however, extinction was significantly less using orange background during extinction compared to the blue background. The present findings suggest that extinction of conditioned eyeblinks depends on the physical context. Findings add to the animal literature that context can play a role in the acquisition of classically conditioned eyeblink responses. Future studies, however, need to be performed to confirm the present findings. Lack of renewal effect may be explained by the highly overlearned character of the VTER.

A comparison of the short- and long-term effects of corticosterone exposure on extinction in adolescence versus adulthood.

PubMed

Den, Miriam Liora; Altmann, Sarah R; Richardson, Rick

2014-12-01

Human and nonhuman adolescents have impaired retention of extinction of learned fear, relative to juveniles and adults. It is unknown whether exposure to stress affects extinction differently in adolescents versus adults. These experiments compared the short- and long-term effects of exposure to the stress-related hormone corticosterone (CORT) on the extinction of learned fear in adolescent and adult rats. Across all experiments, adolescent and adult rats were trained to exhibit good extinction retention by giving extinction training across 2 consecutive days. Despite this extra training, adolescents exposed to 1 week of CORT (200 μg/ml) in their drinking water showed impaired extinction retention when trained shortly after the CORT was removed (Experiment 1a). In contrast, adult rats exposed to CORT (200 μg/ml) for the same duration did not exhibit deficits in extinction retention (Experiment 1b). Exposing adolescents to half the amount of CORT (100 μg/ml; Experiment 1c) for 1 week similarly disrupted extinction retention. Extinction impairments in adult rats were only observed after 3 weeks, rather than 1 week, of CORT (200 μg/ml; Experiment 1d). Remarkably, however, adult rats showed impaired extinction retention if they had been exposed to 1 week of CORT (200 μg/ml) during adolescence (Experiment 2). Finally, exposure to 3 weeks of CORT (200 μg/ml) in adulthood led to long-lasting extinction deficits after a 6-week drug-free period (Experiment 3). These findings suggest that although CORT disrupts both short- and long-term extinction retention in adolescents and adults, adolescents may be more vulnerable to these effects because of the maturation of stress-sensitive brain regions. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats.

PubMed

Zbukvic, Isabel C; Ganella, Despina E; Perry, Christina J; Madsen, Heather B; Bye, Christopher R; Lawrence, Andrew J; Kim, Jee Hyun

2016-06-01

Adolescent drug users display resistance to treatment such as cue exposure therapy (CET), as well as increased liability to relapse. The basis of CET is extinction learning, which involves dopamine signaling in the medial prefrontal cortex (mPFC). This system undergoes dramatic alterations during adolescence. Therefore, we investigated extinction of a cocaine-associated cue in adolescent and adult rats. While cocaine self-administration and lever-alone extinction were not different between the two ages, we observed that cue extinction reduced cue-induced reinstatement in adult but not adolescent rats. Infusion of the selective dopamine 2 receptor (D2R)-like agonist quinpirole into the infralimbic cortex (IL) of the mPFC prior to cue extinction significantly reduced cue-induced reinstatement in adolescents. This effect was replicated by acute systemic treatment with the atypical antipsychotic aripiprazole (Abilify), a partial D2R-like agonist. These data suggest that adolescents may be more susceptible to relapse due to a deficit in cue extinction learning, and highlight the significance of D2R signaling in the IL for cue extinction during adolescence. These findings inspire new tactics for improving adolescent CET, with aripiprazole representing an exciting potential pharmacological adjunct for behavioral therapy. © The Author 2016. Published by Oxford University Press.

Extinction and spontaneous recovery of spatial behavior in pigeons.

PubMed

Leising, Kenneth J; Wong, Jared; Blaisdell, Aaron P

2015-10-01

We investigated extinction and spontaneous recovery of spatial associations using a landmark-based appetitive search task in a touchscreen preparation with pigeons. Four visual landmarks (A, B, C, and D) were separately established as signals of a hidden reinforced target among an 8 × 7 array of potential target locations. The target was located above landmarks (LM) A and C and below B and D. After conditioning, A and B were extinguished. Responding to A and C was assessed on probe tests 2 days following extinction, whereas, B and D were tested 14 days after extinction. We observed spontaneous recovery from spatial extinction following a 14-day, but not a 2-day, postextinction retention interval. Furthermore, by plotting the spatial distribution of responding across the X and Y axes during testing, we found that spontaneous recovery of responding to the target in our task was due to enhanced spatial control (i.e., a change in the overall distribution of responses) following the long delay to testing. These results add spatial extinction and spontaneous recovery to the list of findings supporting the assertion that extinction involves new learning that attenuates the originally acquired response, and that original learning of the spatial relationship between paired events survives extinction. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Emotional trait and memory associates of sleep timing and quality

PubMed Central

Pace-Schott, Edward F.; Rubin, Zoe S.; Tracy, Lauren E.; Spencer, Rebecca M.C.; Orr, Scott P.; Verga, Patrick W.

2015-01-01

Poor ability to remember the extinction of conditioned fear, elevated trait anxiety, and delayed or disrupted nocturnal sleep are reported in anxiety disorders. The current study examines the interrelationship of these factors in healthy young-adult males. Skin- conductance response was conditioned to two differently colored lamps. One color but not the other was then extinguished. After varying delays, both colors were presented to determine extinction recall and generalization. Questionnaires measured sleep quality, morningness - eveningness, neuroticism and trait anxiety. A subset produced a mean 7.0 nights of actigraphy and sleep diaries. Median split of mean sleep midpoint defined early-and late-”sleep timers”. Extinction was more rapidly learned in the morning than evening only in early-timers, who also better generalized extinction recall. Extinction recall was greater with higher sleep efficiency. Sleep efficiency and morningness were negatively associated with neuroticism and anxiety. However, neuroticism and anxiety did not predict extinction learning, recall or generalization. Therefore, neuroticism/anxiety and deficient fear extinction, although both associated with poor quality and late timing of sleep, are not directly associated with each other. Elevated trait anxiety, in addition to predisposing directly to anxiety disorders, may thus also indirectly promote such disorders by impairing sleep and, consequently, extinction memory. PMID:26257092

Emotional trait and memory associates of sleep timing and quality.

PubMed

Pace-Schott, Edward F; Rubin, Zoe S; Tracy, Lauren E; Spencer, Rebecca M C; Orr, Scott P; Verga, Patrick W

2015-10-30

Poor ability to remember the extinction of conditioned fear, elevated trait anxiety, and delayed or disrupted nocturnal sleep are reported in anxiety disorders. The current study examines the interrelationship of these factors in healthy young-adult males. Skin-conductance response was conditioned to two differently colored lamps. One color but not the other was then extinguished. After varying delays, both colors were presented to determine extinction recall and generalization. Questionnaires measured sleep quality, morningness-eveningness, neuroticism and trait anxiety. A subset produced a mean 7.0 nights of actigraphy and sleep diaries. Median split of mean sleep midpoint defined early- and late-"sleep timers". Extinction was more rapidly learned in the morning than evening only in early timers who also better generalized extinction recall. Extinction recall was greater with higher sleep efficiency. Sleep efficiency and morningness were negatively associated with neuroticism and anxiety. However, neuroticism and anxiety did not predict extinction learning, recall or generalization. Therefore, neuroticism/anxiety and deficient fear extinction, although both associated with poor quality and late timing of sleep, are not directly associated with each other. Elevated trait anxiety, in addition to predisposing directly to anxiety disorders, may thus also indirectly promote such disorders by impairing sleep and, consequently, extinction memory. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Differential regulation of glutamic acid decarboxylase gene expression after extinction of a recent memory vs. intermediate memory.

PubMed

Sangha, Susan; Ilenseer, Jasmin; Sosulina, Ludmila; Lesting, Jörg; Pape, Hans-Christian

2012-04-17

Extinction reduces fear to stimuli that were once associated with an aversive event by no longer coupling the stimulus with the aversive event. Extinction learning is supported by a network comprising the amygdala, hippocampus, and prefrontal cortex. Previous studies implicate a critical role of GABA in extinction learning, specifically the GAD65 isoform of the GABA synthesizing enzyme glutamic acid decarboxylase (GAD). However, a detailed analysis of changes in gene expression of GAD in the subregions comprising the extinction network has not been undertaken. Here, we report changes in gene expression of the GAD65 and GAD67 isoforms of GAD, as measured by relative quantitative real-time RT-PCR, in subregions of the amygdala, hippocampus, and prefrontal cortex 24-26 h after extinction of a recent (1-d) or intermediate (14-d) fear memory. Our results show that extinction of a recent memory induces a down-regulation of Gad65 gene expression in the hippocampus (CA1, dentate gyrus) and an up-regulation of Gad67 gene expression in the infralimbic cortex. Extinguishing an intermediate memory increased Gad65 gene expression in the central amygdala. These results indicate a differential regulation of Gad gene expression after extinction of a recent memory vs. intermediate memory.

Compound stimulus presentation and the norepinephrine reuptake inhibitor atomoxetine enhance long-term extinction of cocaine-seeking behavior.

PubMed

Janak, Patricia H; Bowers, M Scott; Corbit, Laura H

2012-03-01

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

Abnormal fear circuitry in Attention Deficit Hyperactivity Disorder: A controlled magnetic resonance imaging study.

PubMed

Spencer, Andrea E; Marin, Marie-France; Milad, Mohammed R; Spencer, Thomas J; Bogucki, Olivia E; Pope, Amanda L; Plasencia, Natalie; Hughes, Brittany; Pace-Schott, Edward F; Fitzgerald, Maura; Uchida, Mai; Biederman, Joseph

2017-04-30

We examined whether non-traumatized subjects with Attention Deficit Hyperactivity Disorder (ADHD) have dysfunctional activation in brain structures mediating fear extinction, possibly explaining the statistical association between ADHD and other disorders characterized by aberrant fear processing such as PTSD. Medication naïve, non-traumatized young adult subjects with (N=27) and without (N=20) ADHD underwent a 2-day fear conditioning and extinction protocol in a 3T functional magnetic resonance imaging (fMRI) scanner. Skin conductance response (SCR) was recorded as a measure of conditioned response. Compared to healthy controls, ADHD subjects had significantly greater insular cortex activation during early extinction, lesser dorsal anterior cingulate cortex (dACC) activation during late extinction, lesser ventromedial prefrontal cortex (vmPFC) activation during late extinction learning and extinction recall, and greater hippocampal activation during extinction recall. Hippocampal and vmPFC deficits were similar to those documented in PTSD subjects compared to traumatized controls without PTSD. Non-traumatized, medication naive adults with ADHD had abnormalities in fear circuits during extinction learning and extinction recall, and some findings were consistent with those previously documented in subjects with PTSD compared to traumatized controls without PTSD. These findings could explain the significant association between ADHD and PTSD as well as impaired emotion regulation in ADHD. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Dopamine D1 receptor agonist treatment attenuates extinction of morphine conditioned place preference while increasing dendritic complexity in the nucleus accumbens core.

PubMed

Kobrin, Kendra L; Arena, Danielle T; Heinrichs, Stephen C; Nguyen, Olivia H; Kaplan, Gary B

2017-03-30

The dopamine D1 receptor (D1R) has a role in opioid reward and conditioned place preference (CPP), but its role in CPP extinction is undetermined. We examined the effect of D1R agonist SKF81297 on the extinction of opioid CPP and associated dendritic morphology in the nucleus accumbens (NAc), a region involved with reward integration and its extinction. During the acquisition of morphine CPP, mice received morphine and saline on alternate days; injections were given immediately before each of eight daily conditioning sessions. Mice subsequently underwent six days of extinction training designed to diminish the previously learned association. Mice were treated with either 0.5mg/kg SKF81297, 0.8mg/kg SKF81297, or saline immediately after each extinction session. There was a dose-dependent effect, with the highest dose of SKF81297 attenuating extinction, as mice treated with this dose had significantly higher CPP scores than controls. Analysis of medium spiny neuron morphology revealed that in the NAc core, but not in the shell, dendritic arbors were significantly more complex in the morphine conditioned, SKF81297-treated mice compared to controls. In separate experiments using mice conditioned with only saline, SKF81297 administration after extinction sessions had no effect on CPP and produced differing effects on dendritic morphology. At the doses used in our experiments, SKF81297 appears to maintain previously learned opioid conditioned behavior, even in the face of new information. The D1R agonist's differential, rather than unidirectional, effects on dendritic morphology in the NAc core suggests that it may be involved in encoding reward information depending on previously learned behavior. Published by Elsevier B.V.

MicroRNA-Mediated Rescue of Fear Extinction Memory by miR-144-3p in Extinction-Impaired Mice.

PubMed

Murphy, Conor P; Li, Xiang; Maurer, Verena; Oberhauser, Michael; Gstir, Ronald; Wearick-Silva, Luis Eduardo; Viola, Thiago Wendt; Schafferer, Simon; Grassi-Oliveira, Rodrigo; Whittle, Nigel; Hüttenhofer, Alexander; Bredy, Timothy W; Singewald, Nicolas

2017-06-15

MicroRNA (miRNA)-mediated control of gene expression suggests that miRNAs are interesting targets and/or biomarkers in the treatment of anxiety- and trauma-related disorders, where often memory-associated gene expression is adversely affected. The role of miRNAs in the rescue of impaired fear extinction was assessed using the 129S1/SvlmJ (S1) mouse model of impaired fear extinction. miRNA microarray analysis, reverse transcription polymerase chain reaction, fluorescent in situ hybridization, lentiviral overexpression, and Luciferase reporter assays were used to gain insight into the mechanisms underlying miRNA-mediated normalization of deficient fear extinction. Rescuing impaired fear extinction via dietary zinc restriction was associated with differential expression of miRNAs in the amygdala. One candidate, miR-144-3p, robustly expressed in the basolateral amygdala, showed specific extinction-induced, but not fear-induced, increased expression in both extinction-rescued S1 mice and extinction-intact C57BL/6 (BL6) mice. miR-144-3p upregulation and effects on subsequent behavioral adaption was assessed in S1 and BL6 mice. miR-144-3p overexpression in the basolateral amygdala rescued impaired fear extinction in S1 mice, led to enhanced fear extinction acquisition in BL6 mice, and furthermore protected against fear renewal in BL6 mice. miR-144-3p targets a number of genes implicated in the control of plasticity-associated signaling cascades, including Pten, Spred1, and Notch1. In functional interaction studies, we revealed that the miR-144-3p target, PTEN, colocalized with miR-144-3p in the basolateral amygdala and showed functional downregulation following successful fear extinction in S1 mice. These findings identify a fundamental role of miR-144-3p in the rescue of impaired fear extinction and suggest this miRNA as a viable target in developing novel treatments for posttraumatic stress disorder and related disorders. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Activation of orexin/hypocretin neurons is associated with individual differences in cued fear extinction.

PubMed

Sharko, Amanda C; Fadel, Jim R; Kaigler, Kris F; Wilson, Marlene A

2017-09-01

Identifying the neurobiological mechanisms that underlie differential sensitivity to stress is critical for understanding the development and expression of stress-induced disorders, such as post-traumatic stress disorder (PTSD). Preclinical studies have suggested that rodents display different phenotypes associated with extinction of Pavlovian conditioned fear responses, with some rodent populations being resistant to extinction. An emerging literature also suggests a role for orexins in the consolidation processes associated with fear learning and extinction. To examine the possibility that the orexin system might be involved in individual differences in fear extinction, we used a Pavlovian conditioning paradigm in outbred Long-Evans rats. Rats showed significant variability in the extinction of cue-conditioned freezing and extinction recall, and animals were divided into groups based on their extinction profiles based on a median split of percent freezing behavior during repeated exposure to the conditioned cue. Animals resistant to extinction (high freezers) showed more freezing during repeated cue presentations during the within trial and between trial extinction sessions compared with the group showing significant extinction (low freezers), although there were no differences between these groups in freezing upon return to the conditioned context or during the conditioning session. Following the extinction recall session, activation of orexin neurons was determined using dual label immunohistochemistry for cFos in orexin positive neurons in the hypothalamus. Individual differences in the extinction of cue conditioned fear were associated with differential activation of hypothalamic orexin neurons. Animals showing poor extinction of cue-induced freezing (high freezers) had significantly greater percentage of orexin neurons with Fos in the medial hypothalamus than animals displaying significant extinction and good extinction recall (low freezers). Further, the freezing during extinction learning was positively correlated with the percentage of activated orexin neurons in both the lateral and medial hypothalamic regions. No differences in the overall density of orexin neurons or Fos activation were seen between extinction phenotypes. Although correlative, our results support other studies implicating a role of the orexinergic system in regulating extinction of conditioned responses to threat. Copyright © 2016 Elsevier Inc. All rights reserved.

Negative appraisals and fear extinction are independently related to PTSD symptoms.

PubMed

Zuj, Daniel V; Palmer, Matthew A; Gray, Kate E; Hsu, Chia-Ming K; Nicholson, Emma L; Malhi, Gin S; Bryant, Richard A; Felmingham, Kim L

2017-08-01

Considerable research has revealed impaired fear extinction to be a significant predictor of PTSD. Fear extinction is also considered the primary mechanism of exposure therapy, and a critical factor in PTSD recovery. The cognitive theory of PTSD proposes that symptoms persist due to excessive negative appraisals about the trauma and its sequelae. Research has not yet examined the relationship between fear extinction and negative appraisals in PTSD. A cross-sectional sample of participants with PTSD (n =21), and trauma-exposed controls (n =33) underwent a standardized differential fear conditioning and extinction paradigm, with skin conductance response (SCR) amplitude serving as the index of conditioned responses. The Posttraumatic Cognitions Inventory (PTCI) was used to index catastrophic negative appraisals. Participants with PTSD demonstrated a slower decrease in overall SCR responses during extinction and greater negative appraisals compared to the group. A moderation analysis revealed that both negative trauma-relevant appraisals and fear extinction learning were independently associated with PTSD symptoms, but there was no moderation interaction. The current study was limited by a modest sample size, leading to the inclusion of participants with subclinical PTSD symptoms. Further, the current study only assessed fear extinction learning; including a second day extinction recall task may show alternative effects. These findings indicate that negative appraisals and fear extinction did not interact, but had independent relationships with PTSD symptoms. Here we show for the first time in an experimental framework that negative appraisals and fear extinction play separate roles in PTSD symptoms. Copyright © 2017 Elsevier B.V. All rights reserved.

Learning and owner-stranger effects on interspecific communication in domestic dogs (Canis familiaris).

PubMed

Elgier, Angel M; Jakovcevic, Adriana; Mustaca, Alba E; Bentosela, Mariana

2009-05-01

Domestic dogs are very successful at following human cues like gazing or pointing to find hidden food in an object choice task. They solve this kind of situation at their first attempts and from early stages of their development and perform better than wolves. Most of the authors proposed that these abilities are a domestication product, and independent from learning processes. There are few systematic studies on the effects of learning on dogs' communicative skills. We aim to evaluate the effect of extinction and reversal learning procedures on the use of the pointing gesture in an object choice task. The results showed that dogs stopped following the pointing cue in the extinction and that they learned to choose the not pointed container in the reversal learning. Results suggest that instrumental learning plays an important role in interspecific communication mechanisms between humans and dogs. In both experiments for half of the subjects the pointer was the owner and for the rest was a stranger. A differential effect was found: extinction was slower but reversal learning was faster when the owner gave the cue. This data indicates that the relationship of the dog with the person who emits the cue influences performance.

Prefrontal single-unit firing associated with deficient extinction in mice

PubMed Central

Fitzgerald, Paul J; Whittle, Nigel; Flynn, Shaun M; Graybeal, Carolyn; Pinard, Courtney; Gunduz-Cinar, Ozge; Kravitz, Alexxai; Singewald, Nicolas; Holmes, Andrew

2014-01-01

The neural circuitry mediating fear extinction has been increasingly well studied and delineated. The rodent infralimbic subregion (IL) of the ventromedial prefrontal cortex (vmPFC) has been found to promote extinction, whereas the prelimbic cortex (PL) demonstrates an opposing, pro-fear, function. Studies employing in vivo electrophysiological recordings have observed that while increased IL single-unit firing and bursting predicts robust extinction retrieval, increased PL firing can correlate with sustained fear and poor extinction. These relationships between single-unit firing and extinction do not hold under all experimental conditions, however. In the current study, we further investigated the relationship between vmPFC and PL single-unit firing and extinction using inbred mouse models of intact (C57BL/6J, B6) and deficient (129S1/SvImJ, S1) extinction strains. Simultaneous single-unit recordings were made in the PL and vmPFC (encompassing IL) as B6 and S1 mice performed extinction training and retrieval. Impaired extinction retrieval in S1 mice was associated with elevated PL single-unit firing, as compared to firing in extinguishing B6 mice, consistent with the hypothesized pro-fear contribution of PL. Analysis of local field potentials also revealed significantly higher gamma power in the PL of Sthan B6 mice during extinction training and retrieval. In the vmPFC, impaired extinction in S1 mice was also associated with exaggerated single-unit firing, relative to B6 mice. This is in apparent contradiction to evidence that IL activity promotes extinction, but could reflect a (failed) compensatory effort by the vmPFC to mitigate fear-promoting activity in other regions, such as the PL or amygdala. In support of this hypothesis, augmenting IL activity via direct infusion of the GABAA receptor antagonist picrotoxin rescued impaired extinction retrieval in S1 mice. Chronic fluoxetine treatment produced modest reductions in fear during extinction retrieval and increased the number of Zif268-labeled cells in layer II of IL, but failed to increase vmPFC single-unit firing. Collectively, these findings further support the important contribution these cortical regions play in determining the balance between robust extinction on the one hand, and sustained fear on the other. Elucidating the precise nature of these roles could help inform understanding of the pathophysiology of fear-related anxiety disorders. PMID:24231425

Recording single neurons' action potentials from freely moving pigeons across three stages of learning.

PubMed

Starosta, Sarah; Stüttgen, Maik C; Güntürkün, Onur

2014-06-02

While the subject of learning has attracted immense interest from both behavioral and neural scientists, only relatively few investigators have observed single-neuron activity while animals are acquiring an operantly conditioned response, or when that response is extinguished. But even in these cases, observation periods usually encompass only a single stage of learning, i.e. acquisition or extinction, but not both (exceptions include protocols employing reversal learning; see Bingman et al.(1) for an example). However, acquisition and extinction entail different learning mechanisms and are therefore expected to be accompanied by different types and/or loci of neural plasticity. Accordingly, we developed a behavioral paradigm which institutes three stages of learning in a single behavioral session and which is well suited for the simultaneous recording of single neurons' action potentials. Animals are trained on a single-interval forced choice task which requires mapping each of two possible choice responses to the presentation of different novel visual stimuli (acquisition). After having reached a predefined performance criterion, one of the two choice responses is no longer reinforced (extinction). Following a certain decrement in performance level, correct responses are reinforced again (reacquisition). By using a new set of stimuli in every session, animals can undergo the acquisition-extinction-reacquisition process repeatedly. Because all three stages of learning occur in a single behavioral session, the paradigm is ideal for the simultaneous observation of the spiking output of multiple single neurons. We use pigeons as model systems, but the task can easily be adapted to any other species capable of conditioned discrimination learning.

The Role of the Medial Prefrontal Cortex in Trace Fear Extinction

ERIC Educational Resources Information Center

Kwapis, Janine L.; Jarome, Timothy J.; Helmstetter, Fred J.

2015-01-01

The extinction of delay fear conditioning relies on a neural circuit that has received much attention and is relatively well defined. Whether this established circuit also supports the extinction of more complex associations, however, is unclear. Trace fear conditioning is a better model of complex relational learning, yet the circuit that…

Extinction of opiate reward reduces dendritic arborization and c-Fos expression in the nucleus accumbens core.

PubMed

Leite-Morris, Kimberly A; Kobrin, Kendra L; Guy, Marsha D; Young, Angela J; Heinrichs, Stephen C; Kaplan, Gary B

2014-04-15

Recurrent opiate use combined with environmental cues, in which the drug was administered, provokes cue-induced drug craving and conditioned drug reward. Drug abuse craving is frequently linked with stimuli from a prior drug-taking environment via classical conditioning and associative learning. We modeled the conditioned morphine reward process by using acquisition and extinction of conditioned place preference (CPP) in C57BL/6 mice. Mice were trained to associate a morphine injection with a drug context using a classical conditioning paradigm. In morphine conditioning (0, 0.25, 0.5, 1, 5, or 10 mg/kg) experimental mice acquired a morphine CPP dose response with 10mg/kg as most effective. During morphine CPP extinction experiments, mice were divided into three test groups: morphine CPP followed by extinction training, morphine CPP followed by sham extinction, and saline controls. Extinction of morphine CPP developed within one extinction experiment (4 days) that lasted over two more trials (another 8 days). However, the morphine CPP/sham extinction group retained a place preference that endured through all three extinction trials. Brains were harvested following CPP extinction and processed using Golgi-Cox impregnation. Changes in dendritic morphology and spine quantity were examined in the nucleus accumbens (NAc) Core and Shell neurons. In the NAcCore only, morphine CPP/extinguished mice produced less dendritic arborization, and a decrease in neuronal activity marker c-Fos compared to the morphine CPP/sham extinction group. Extinction of morphine CPP is associated with decreased structural complexity of dendrites in the NAcCore and may represent a substrate for learning induced structural plasticity relevant to addiction. Published by Elsevier B.V.

Enhancing and impairing extinction of habit memory through modulation of NMDA receptors in the dorsolateral striatum.

PubMed

Goodman, Jarid; Ressler, Reed L; Packard, Mark G

2017-06-03

The present experiments investigated the involvement of N-methyl-d-aspartate (NMDA) receptors of the dorsolateral striatum (DLS) in consolidation of extinction in a habit memory task. Adult male Long-Evans rats were initially trained in a food-reinforced response learning version of a plus-maze task and were subsequently given extinction training in which the food was removed from the maze. In experiment 1, immediately after the first day of extinction training, rats received bilateral intra-DLS injections of the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP5; 2µg/side) or physiological saline. In experiment 2, immediately following the first day of extinction training, animals were given intra-DLS injections of NMDA receptor partial agonist d-cycloserine (DCS; 10 or 20µg/side) or saline. In both experiments, the number of perseverative trials (a trial in which a rat made the same previously reinforced body-turn response) and latency to reach the previously correct food well were used as measures of extinction behavior. Results indicated that post-training intra-DLS injections of AP5 impaired extinction. In contrast, post-training intra-DLS infusions of DCS (20µg) enhanced extinction. Intra-DLS administration of AP5 or DCS given two hours after extinction training did not influence extinction of response learning, indicating that immediate post-training administration of AP5 and DCS specifically influenced consolidation of the extinction memory. The present results indicate a critical role for DLS NMDA receptors in modulating extinction of habit memory and may be relevant to developing therapeutic approaches to combat the maladaptive habits observed in human psychopathologies in which DLS-dependent memory has been implicated (e.g. drug addiction and relapse and obsessive compulsive disorder). Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Enhancing dopaminergic signaling and histone acetylation promotes long-term rescue of deficient fear extinction

PubMed Central

Whittle, N; Maurer, V; Murphy, C; Rainer, J; Bindreither, D; Hauschild, M; Scharinger, A; Oberhauser, M; Keil, T; Brehm, C; Valovka, T; Striessnig, J; Singewald, N

2016-01-01

Extinction-based exposure therapy is used to treat anxiety- and trauma-related disorders; however, there is the need to improve its limited efficacy in individuals with impaired fear extinction learning and to promote greater protection against return-of-fear phenomena. Here, using 129S1/SvImJ mice, which display impaired fear extinction acquisition and extinction consolidation, we revealed that persistent and context-independent rescue of deficient fear extinction in these mice was associated with enhanced expression of dopamine-related genes, such as dopamine D1 (Drd1a) and -D2 (Drd2) receptor genes in the medial prefrontal cortex (mPFC) and amygdala, but not hippocampus. Moreover, enhanced histone acetylation was observed in the promoter of the extinction-regulated Drd2 gene in the mPFC, revealing a potential gene-regulatory mechanism. Although enhancing histone acetylation, via administering the histone deacetylase (HDAC) inhibitor MS-275, does not induce fear reduction during extinction training, it promoted enduring and context-independent rescue of deficient fear extinction consolidation/retrieval once extinction learning was initiated as shown following a mild conditioning protocol. This was associated with enhanced histone acetylation in neurons of the mPFC and amygdala. Finally, as a proof-of-principle, mimicking enhanced dopaminergic signaling by L-dopa treatment rescued deficient fear extinction and co-administration of MS-275 rendered this effect enduring and context-independent. In summary, current data reveal that combining dopaminergic and epigenetic mechanisms is a promising strategy to improve exposure-based behavior therapy in extinction-impaired individuals by initiating the formation of an enduring and context-independent fear-inhibitory memory. PMID:27922638

Role of medial prefrontal cortex Narp in the extinction of morphine conditioned place preference.

PubMed

Blouin, Ashley M; Han, Sungho; Pearce, Anne M; Cheng, Kailun; Lee, Jongah J; Johnson, Alexander W; Wang, Chuansong; During, Matthew J; Holland, Peter C; Shaham, Yavin; Baraban, Jay M; Reti, Irving M

2013-01-15

Narp knockout (KO) mice demonstrate an impaired extinction of morphine conditioned place preference (CPP). Because the medial prefrontal cortex (mPFC) has been implicated in extinction learning, we tested whether Narp cells in this region play a role in the extinction of morphine CPP. We found that intracranial injections of adenoassociated virus (AAV) expressing wild-type (WT) Narp into the mPFC of Narp KO mice rescued the extinction and the injection of AAV expressing a dominant negative form of Narp (NarpN) into the mPFC of WT mice impaired the extinction of morphine CPP. These findings suggest that Narp in the mPFC mediates the extinction of morphine CPP.

Temporal specificity of extinction in autoshaping.

PubMed

Drew, Michael R; Yang, Cynthia; Ohyama, Tatsuya; Balsam, Peter D

2004-07-01

Three experiments investigated the effects of varying the conditioned stimulus (CS) duration between training and extinction. Ring doves (Streptopelia risoria) were autoshaped on a fixed CS-unconditioned stimulus (US) interval and extinguished with CS presentations that were longer, shorter, or the same as the training duration. During a subsequent test session, the training CS duration was reintroduced. Results suggest that the cessation of responding during an extinction session is controlled by generalization of excitation between the training and extinction CSs and by the number of nonreinforced CS presentations. Transfer of extinction to the training CS is controlled by the similarity between the extinction and training CSs. Extinction learning is temporally specific. (c) 2004 APA, all rights reserved

No impact of repeated extinction exposures on operant responding maintained by different reinforcer rates.

PubMed

Bai, John Y H; Podlesnik, Christopher A

2017-05-01

Greater rates of intermittent reinforcement in the presence of discriminative stimuli generally produce greater resistance to extinction, consistent with predictions of behavioral momentum theory. Other studies reveal more rapid extinction with higher rates of reinforcers - the partial reinforcement extinction effect. Further, repeated extinction often produces more rapid decreases in operant responding due to learning a discrimination between training and extinction contingencies. The present study examined extinction repeatedly with training with different rates of intermittent reinforcement in a multiple schedule. We assessed whether repeated extinction would reverse the pattern of greater resistance to extinction with greater reinforcer rates. Counter to this prediction, resistance to extinction was consistently greater across twelve assessments of training followed by six successive sessions of extinction. Moreover, patterns of responding during extinction resembled those observed during satiation tests, which should not alter discrimination processes with repeated testing. These findings join others suggesting operant responding in extinction can be durable across repeated tests. Copyright © 2017 Elsevier B.V. All rights reserved.

The L-type voltage-gated calcium channel CaV1.2 mediates fear extinction and modulates synaptic tone in the lateral amygdala.

PubMed

Temme, Stephanie J; Murphy, Geoffrey G

2017-11-01

L-type voltage-gated calcium channels (LVGCCs) have been implicated in both the formation and the reduction of fear through Pavlovian fear conditioning and extinction. Despite the implication of LVGCCs in fear learning and extinction, studies of the individual LVGCC subtypes, Ca V 1.2 and Ca V 1.3, using transgenic mice have failed to find a role of either subtype in fear extinction. This discontinuity between the pharmacological studies of LVGCCs and the studies investigating individual subtype contributions could be due to the limited neuronal deletion pattern of the Ca V 1.2 conditional knockout mice previously studied to excitatory neurons in the forebrain. To investigate the effects of deletion of Ca V 1.2 in all neuronal populations, we generated Ca V 1.2 conditional knockout mice using the synapsin1 promoter to drive Cre recombinase expression. Pan-neuronal deletion of Ca V 1.2 did not alter basal anxiety or fear learning. However, pan-neuronal deletion of Ca V 1.2 resulted in a significant deficit in extinction of contextual fear, implicating LVGCCs, specifically Ca V 1.2, in extinction learning. Further exploration on the effects of deletion of Ca V 1.2 on inhibitory and excitatory input onto the principle neurons of the lateral amygdala revealed a significant shift in inhibitory/excitatory balance. Together these data illustrate an important role of Ca V 1.2 in fear extinction and the synaptic regulation of activity within the amygdala. © 2017 Temme and Murphy; Published by Cold Spring Harbor Laboratory Press.

Medial prefrontal cortex circuit function during retrieval and extinction of associative learning under anesthesia.

PubMed

Fenton, G E; Halliday, D M; Mason, R; Stevenson, C W

2014-04-18

Associative learning is encoded under anesthesia and involves the medial prefrontal cortex (mPFC). Neuronal activity in mPFC increases in response to a conditioned stimulus (CS+) previously paired with an unconditioned stimulus (US) but not during presentation of an unpaired stimulus (CS-) in anesthetized animals. Studies in conscious animals have shown dissociable roles for different mPFC subregions in mediating various memory processes, with the prelimbic (PL) and infralimbic (IL) cortex involved in the retrieval and extinction of conditioned responding, respectively. Therefore PL and IL may also play different roles in mediating the retrieval and extinction of discrimination learning under anesthesia. Here we used in vivo electrophysiology to examine unit and local field potential (LFP) activity in PL and IL before and after auditory discrimination learning and during later retrieval and extinction testing in anesthetized rats. Animals received repeated presentations of two distinct sounds, one of which was paired with footshock (US). In separate control experiments animals received footshocks without sounds. After discrimination learning the paired (CS+) and unpaired (CS-) sounds were repeatedly presented alone. We found increased unit firing and LFP power in PL and, to a lesser extent, IL after discrimination learning but not after footshocks alone. After discrimination learning, unit firing and LFP power increased in PL and IL in response to presentation of the first CS+, compared to the first CS-. However, PL and IL activity increased during the last CS- presentation, such that activity during presentation of the last CS+ and CS- did not differ. These results confirm previous findings and extend them by showing that increased PL and IL activity result from encoding of the CS+/US association rather than US presentation. They also suggest that extinction may occur under anesthesia and might be represented at the neural level in PL and IL. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Using a Peer-Mediated Extinction Procedure to Decrease Obscene Language.

ERIC Educational Resources Information Center

Salend, Spencer J.; Meddaugh, Dona

1985-01-01

A peer extinction procedure in which students refrained from laughing at or attending to a targeted student's inappropriate behavior decreased the adolescent learning disabled student's obscene language. (CL)

Competition Between Extinction and Enhancement in Surface Enhanced Raman Spectroscopy.

PubMed

van Dijk, Thomas; Sivapalan, Sean T; Devetter, Brent M; Yang, Timothy K; Schulmerich, Matthew V; Murphy, Catherine J; Bhargava, Rohit; Carney, P Scott

2013-04-04

Conjugated metallic nanoparticles are a promising means to achieve ultrasensitive and multiplexed sensing in intact three-dimensional samples, especially for biological applications, via surface enhanced Raman scattering (SERS). We show that enhancement and extinction are linked and compete in a collection of metallic nanoparticles. Counterintuitively, the Raman signal vanishes when nanoparticles are excited at their plasmon resonance, while increasing nanoparticle concentrations at off-resonance excitation sometimes leads to decreased signal. We develop an effective medium theory that explains both phenomena. Optimal choices of excitation wavelength, individual particle enhancement factor and concentrations are indicated. The same processes which give rise to enhancement also lead to increased extinction of both the illumination and the Raman scattered light. Nanoparticles attenuate the incident field (blue) and at the same time provide local enhancement for SERS. Likewise the radiation of the Raman-scattered field (green) is enhanced by the near-by sphere but extinguished by the rest of the spheres in the suspension on propagation.

Distinct Fos-Expressing Neuronal Ensembles in the Ventromedial Prefrontal Cortex Mediate Food Reward and Extinction Memories

PubMed Central

Warren, Brandon L.; Mendoza, Michael P.; Cruz, Fabio C.; Leao, Rodrigo M.; Caprioli, Daniele; Rubio, F. Javier; Whitaker, Leslie R.; McPherson, Kylie B.; Bossert, Jennifer M.; Shaham, Yavin

2016-01-01

In operant learning, initial reward-associated memories are thought to be distinct from subsequent extinction-associated memories. Memories formed during operant learning are thought to be stored in “neuronal ensembles.” Thus, we hypothesize that different neuronal ensembles encode reward- and extinction-associated memories. Here, we examined prefrontal cortex neuronal ensembles involved in the recall of reward and extinction memories of food self-administration. We first trained rats to lever press for palatable food pellets for 7 d (1 h/d) and then exposed them to 0, 2, or 7 daily extinction sessions in which lever presses were not reinforced. Twenty-four hours after the last training or extinction session, we exposed the rats to either a short 15 min extinction test session or left them in their homecage (a control condition). We found maximal Fos (a neuronal activity marker) immunoreactivity in the ventral medial prefrontal cortex of rats that previously received 2 extinction sessions, suggesting that neuronal ensembles in this area encode extinction memories. We then used the Daun02 inactivation procedure to selectively disrupt ventral medial prefrontal cortex neuronal ensembles that were activated during the 15 min extinction session following 0 (no extinction) or 2 prior extinction sessions to determine the effects of inactivating the putative food reward and extinction ensembles, respectively, on subsequent nonreinforced food seeking 2 d later. Inactivation of the food reward ensembles decreased food seeking, whereas inactivation of the extinction ensembles increased food seeking. Our results indicate that distinct neuronal ensembles encoding operant reward and extinction memories intermingle within the same cortical area. SIGNIFICANCE STATEMENT A current popular hypothesis is that neuronal ensembles in different prefrontal cortex areas control reward-associated versus extinction-associated memories: the dorsal medial prefrontal cortex (mPFC) promotes reward seeking, whereas the ventral mPFC inhibits reward seeking. In this paper, we use the Daun02 chemogenetic inactivation procedure to demonstrate that Fos-expressing neuronal ensembles mediating both food reward and extinction memories intermingle within the same ventral mPFC area. PMID:27335401

Distinct Fos-Expressing Neuronal Ensembles in the Ventromedial Prefrontal Cortex Mediate Food Reward and Extinction Memories.

PubMed

Warren, Brandon L; Mendoza, Michael P; Cruz, Fabio C; Leao, Rodrigo M; Caprioli, Daniele; Rubio, F Javier; Whitaker, Leslie R; McPherson, Kylie B; Bossert, Jennifer M; Shaham, Yavin; Hope, Bruce T

2016-06-22

In operant learning, initial reward-associated memories are thought to be distinct from subsequent extinction-associated memories. Memories formed during operant learning are thought to be stored in "neuronal ensembles." Thus, we hypothesize that different neuronal ensembles encode reward- and extinction-associated memories. Here, we examined prefrontal cortex neuronal ensembles involved in the recall of reward and extinction memories of food self-administration. We first trained rats to lever press for palatable food pellets for 7 d (1 h/d) and then exposed them to 0, 2, or 7 daily extinction sessions in which lever presses were not reinforced. Twenty-four hours after the last training or extinction session, we exposed the rats to either a short 15 min extinction test session or left them in their homecage (a control condition). We found maximal Fos (a neuronal activity marker) immunoreactivity in the ventral medial prefrontal cortex of rats that previously received 2 extinction sessions, suggesting that neuronal ensembles in this area encode extinction memories. We then used the Daun02 inactivation procedure to selectively disrupt ventral medial prefrontal cortex neuronal ensembles that were activated during the 15 min extinction session following 0 (no extinction) or 2 prior extinction sessions to determine the effects of inactivating the putative food reward and extinction ensembles, respectively, on subsequent nonreinforced food seeking 2 d later. Inactivation of the food reward ensembles decreased food seeking, whereas inactivation of the extinction ensembles increased food seeking. Our results indicate that distinct neuronal ensembles encoding operant reward and extinction memories intermingle within the same cortical area. A current popular hypothesis is that neuronal ensembles in different prefrontal cortex areas control reward-associated versus extinction-associated memories: the dorsal medial prefrontal cortex (mPFC) promotes reward seeking, whereas the ventral mPFC inhibits reward seeking. In this paper, we use the Daun02 chemogenetic inactivation procedure to demonstrate that Fos-expressing neuronal ensembles mediating both food reward and extinction memories intermingle within the same ventral mPFC area. Copyright © 2016 the authors 0270-6474/16/366691-13$15.00/0.

Tactile learning and the individual evaluation of the reward in honey bees (Apis mellifera L.).

PubMed

Scheiner, R; Erber, J; Page, R E

1999-07-01

Using the proboscis extension response we conditioned pollen and nectar foragers of the honey bee (Apis mellifera L.) to tactile patterns under laboratory conditions. Pollen foragers demonstrated better acquisition, extinction, and reversal learning than nectar foragers. We tested whether the known differences in response thresholds to sucrose between pollen and nectar foragers could explain the observed differences in learning and found that nectar foragers with low response thresholds performed better during acquisition and extinction than ones with higher thresholds. Conditioning pollen and nectar foragers with similar response thresholds did not yield differences in their learning performance. These results suggest that differences in the learning performance of pollen and nectar foragers are a consequence of differences in their perception of sucrose. Furthermore, we analysed the effect which the perception of sucrose reward has on associative learning. Nectar foragers with uniform low response thresholds were conditioned using varying concentrations of sucrose. We found significant positive correlations between the concentrations of the sucrose rewards and the performance during acquisition and extinction. The results are summarised in a model which describes the relationships between learning performance, response threshold to sucrose, concentration of sucrose and the number of rewards.

Effects of prenatal chronic mild stress exposure on hippocampal cell proliferation, expression of GSK-3α, β and NR2B in adult offspring during fear extinction in rats.

PubMed

Li, Min; Li, Xiaobai; Zhang, Xinxin; Ren, Jintao; Jiang, Han; Wang, Yan; Ma, Yuchao; Cheng, Wenwen

2014-06-01

Stress during pregnancy has been implicated as a risk factor for the development of many mental disorders; however, the influence of prenatal stress on the fear or anxiety-related behaviors, especially the fear extinction in adult offspring has been little investigated. In order to investigate how prenatal stress affects fear extinction, which is regarded as a form of new learning that counteracts the expression of Pavlovian's conditioned fear, a rat model of prenatal chronic mild stress (PNS) was used to evaluate the effects of PNS on fear extinction in adult offspring. The expression of hippocampal glycogen synthase kinase-3s (GSK-3α, β), N-methyl-d-aspartic acid receptors (NMDARs)-2B and the hippocampal cell proliferation in dentate gyrus in the adult offspring during fear extinction were studied. Our results showed that PNS significantly reduced body weight of pups, indicating PNS might induce growth retardation in offspring. Moreover, PNS significantly enhanced the freezing behavior of offspring at the phase of extinction, suggesting PNS impaired the abilities of fear extinction learning. In addition, PNS significantly increased the levels of GSK-3α, β and NR2B, but reduced hippocampal cell proliferation during fear extinction. Taken together, our findings suggest that maternal stress during pregnancy can impair the fear extinction of adult offspring, probably by affecting the neural plasticity of brain. Copyright © 2014 ISDN. Published by Elsevier Ltd. All rights reserved.

Selective and Protracted Effect of Nifedipine on Fear Memory Extinction Correlates with Induced Stress Response

ERIC Educational Resources Information Center

Waltereit, Robert; Mannhardt, Sonke; Nescholta, Sabine; Maser-Gluth, Christiane; Bartsch, Dusan

2008-01-01

Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage…

Reexposure to the Amnestic Agent Alleviates Cycloheximide-Induced Retrograde Amnesia for Reactivated and Extinction Memories

ERIC Educational Resources Information Center

Briggs, James F.; Olson, Brian P.

2013-01-01

We investigated whether reexposure to an amnestic agent would reverse amnesia for extinction of learned fear similar to that of a reactivated memory. When cycloheximide (CHX) was administered immediately after a brief cue-induced memory reactivation (15 sec) and an extended extinction session (12 min) rats showed retrograde amnesia for both…

Translation of associative learning models into extinction reminders delivered via mobile phones during cue exposure interventions for substance use.

PubMed

Rosenthal, M Zachary; Kutlu, Munir G

2014-09-01

Despite experimental findings and some treatment research supporting the use of cues as a means to induce and extinguish cravings, interventions using cue exposure have not been well integrated into contemporary substance abuse treatments. A primary problem with exposure-based interventions for addiction is that after learning not to use substances in the presence of addiction cues inside the clinic (i.e., extinction), stimuli in the naturalistic setting outside the clinic may continue to elicit craving, drug use, or other maladaptive conditioned responses. For exposure-based substance use interventions to be efficacious, new approaches are needed that can prevent relapse by directly generalizing learning from the therapeutic setting into naturalistic settings associated with a high risk for relapse. Basic research suggests that extinction reminders (ERs) can be paired with the context of learning new and more adaptive conditioned responses to substance abuse cues in exposure therapies for addiction. Using mobile phones and automated dialing and data collection software, ERs can be delivered in everyday high-risk settings to inhibit conditioned responses to substance-use-related stimuli. In this review, we describe how associative learning mechanisms (e.g., conditioned inhibition) can inform how ERs are conceptualized, learned, and implemented to prevent substance use when delivered via mobile phones. This approach, exposure with portable reminders of extinction, is introduced as an adjunctive intervention that uses brief automated ERs between clinic visits when individuals are in high-risk settings for drug use.

Worrying affects associative fear learning: a startle fear conditioning study.

PubMed

Gazendam, Femke J; Kindt, Merel

2012-01-01

A valuable experimental model for the pathogenesis of anxiety disorders is that they originate from a learned association between an intrinsically non-aversive event (Conditioned Stimulus, CS) and an anticipated disaster (Unconditioned Stimulus, UCS). Most anxiety disorders, however, do not evolve from a traumatic experience. Insights from neuroscience show that memory can be modified post-learning, which may elucidate how pathological fear can develop after relatively mild aversive events. Worrying--a process frequently observed in anxiety disorders--is a potential candidate to strengthen the formation of fear memory after learning. Here we tested in a discriminative fear conditioning procedure whether worry strengthens associative fear memory. Participants were randomly assigned to either a Worry (n = 23) or Control condition (n = 25). After fear acquisition, the participants in the Worry condition processed six worrisome questions regarding the personal aversive consequences of an electric stimulus (UCS), whereas the Control condition received difficult but neutral questions. Subsequently, extinction, reinstatement and re-extinction of fear were tested. Conditioned responding was measured by fear-potentiated startle (FPS), skin conductance (SCR) and UCS expectancy ratings. Our main results demonstrate that worrying resulted in increased fear responses (FPS) to both the feared stimulus (CS(+)) and the originally safe stimulus (CS(-)), whereas FPS remained unchanged in the Control condition. In addition, worrying impaired both extinction and re-extinction learning of UCS expectancy. The implication of our findings is that they show how worry may contribute to the development of anxiety disorders by affecting associative fear learning.

Extinction of specific stimulus-outcome (S-O) associations in Pavlovian learning with an extended CS procedure.

PubMed

Delamater, Andrew R; Schneider, Kevin; Derman, Rifka C

2017-07-01

Three experiments with male and female rats were conducted to examine the effects of Pavlovian extinction training on Pavlovian-to-instrumental transfer (PIT) in a task in which the unconditioned stimulus (US) was presented at an early time point within an extended conditioned stimulus (CS). Two instrumental responses were trained with different reinforcing outcomes (R1-O1, R2-O2) and then, independently, 2 stimuli were trained with those outcomes (S1-O1, S2-O2). One group then underwent an extinction treatment (S1-, S2-) and a second was merely exposed to the experimental contexts without any stimulus events. Finally, the effects of the 2 stimuli on instrumental responding were assessed in PIT tests. Across experiments we varied the number of Pavlovian training trials prior to extinction (8, 16, or 64 trials) and the length of time following extinction prior to test (i.e., 1 or 21 days, in a test for spontaneous recovery). We observed that outcome-specific PIT was reduced by extinction in all of our training conditions and that this extinction effect was durable, surviving a 3-week spontaneous recovery interval even though conditioned magazine approach spontaneously recovered over this interval. Although extinction reduced the magnitude of PIT, the temporal expression of PIT was mostly unaffected. We found these effects in both male and female rats, though in 1 study females were extinction-resistant. These data suggest that under the conditions studied here Pavlovian extinction may permanently weaken the ability of Pavlovian cues to retrieve a representation of their associated outcomes without impacting the temporal organization of responding. This suggests that different features of learning may be differentially sensitive to extinction. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Stress exposure prior to fear acquisition interacts with estradiol status to alter recall of fear extinction in humans.

PubMed

Antov, Martin I; Stockhorst, Ursula

2014-11-01

Classical fear acquisition and extinction are important models for the etiology and treatment of anxiety disorders such as posttraumatic stress disorder (PTSD). Women are at a higher risk for PTSD than men. Levels of circulating 17-β estradiol (E2) in women have been linked to deficits in fear extinction and extinction recall. In PTSD, fear learning coincides with acute traumatic stress. However, little is known about the possible interaction between stress exposure and hormone status on fear acquisition and extinction learning. In a 2-day, 2×3 between-subjects design with healthy participants, we examined the effects of stress (psychosocial stressor vs. control, placed 45 min prior to conditioning) and natural E2-status on differential fear conditioning, covering fear acquisition, immediate extinction (Day 1), and 24h-delayed extinction recall (Day 2). To operationalize E2-status, we compared women in the early follicular phase (EF) of their menstrual cycle (low E2, low progesterone plasma levels), women in the midcycle phase (MC, high E2, low progesterone), and men. Conditioning was indicated by differential skin conductance responses. We found an interaction between stress exposure and natural E2-status in women only: In MC-women, extinction recall on Day 2 (24h after initial extinction training) was better when fear acquisition had been preceded by stress. In EF-women, the inverse was true. We show that extinction recall of conditioned fear acquired after stress depends on estrogen status in women. Therefore, extinction-based exposure therapy in free-cycling female anxiety patients should take cycle status into account. Copyright © 2014 Elsevier Ltd. All rights reserved.

Plastic Synaptic Networks of the Amygdala for the Acquisition, Expression, and Extinction of Conditioned Fear

PubMed Central

Pape, Hans-Christian; Pare, Denis

2009-01-01

The last ten years have witnessed a surge of interest for the mechanisms underlying the acquisition and extinction of classically conditioned fear responses. In part, this results from the realization that abnormalities in fear learning mechanisms likely participate to the development and/or maintenance of human anxiety disorders. The simplicity and robustness of this learning paradigm, coupled to the fact that the underlying circuitry is evolutionarily well conserved makes it an ideal model to study the basic biology of memory and identify genetic factors and neuronal systems that regulate the normal and pathological expressions of learned fear. Critical advances have been made in determining how modified neuronal functions upon fear acquisition become stabilized during fear memory consolidation and how these processes are controlled in the course of fear memory extinction. With these advances, came the realization that activity in remote neuronal networks must be coordinated for these events to take place. In this paper, we review these mechanisms of coordinated network activity and the molecular cascades leading to enduring fear memory, and allowing for their extinction. We will focus on Pavlovian fear conditioning as a model and the amygdala as a key component for the acquisition and extinction of fear responses. PMID:20393190

Extinction and the associative structure of heterogeneous instrumental chains.

PubMed

Thrailkill, Eric A; Bouton, Mark E

2016-09-01

Drug abuse, overeating, and smoking are all examples of instrumental behaviors that often involve chains or sequences of behavior. A behavior chain is minimally composed of a procurement response that is required in order for a subsequent consumption response to be reinforced. Despite the translational importance of behavior chains, few studies have attempted to understand what binds them together and takes them apart. This article surveys the development of the heterogeneous instrumental chain method and introduces recent findings that have used extinction to analyze the associative content of (what is learned in) the chain. Chained responses that are occasion-set by their own discriminative stimuli may be directly associated; extinction of the procurement response weakens its associated consumption response, and extinction of the consumption response weakens its associated procurement response. Extinction itself involves learning to inhibit the response. Extinguished chained responses are subject to renewal when they are tested either back in the acquisition context or in a new context. In addition, a consumption response that is extinguished outside its chain is renewed when returned to the context of the preceding response in the chain. Research on heterogeneous behavior chains can provide important insights into an important but often overlooked aspect of instrumental learning. Copyright © 2016 Elsevier Inc. All rights reserved.

Haploinsufficiency of VGluT1 but not VGluT2 impairs extinction of spatial preference and response suppression.

PubMed

Callaerts-Vegh, Zsuzsanna; Moechars, Diederik; Van Acker, Nathalie; Daneels, Guy; Goris, Ilse; Leo, Sandra; Naert, Arne; Meert, Theo; Balschun, Detlef; D'Hooge, Rudi

2013-05-15

The excitatory neurotransmitter l-glutamate is transported into synaptic vesicles by vesicular glutamate transporters (VGluTs) to transmit glutamatergic signals. Changes in their expression have been linked to various brain disorders including schizophrenia, Parkinson's, and Alzheimer's disease. Deleting either the VGluT1 or VGluT2 gene leads to profound developmental and neurological complications and early death, but mice heterozygous for VGluT1 or VGluT2 are viable and thrive. Acquisition, retention and extinction of conditioned visuospatial and emotional responses were compared between VGluT1(+/-) and VGluT2(+/-) mice, and their wildtype littermates, using different water maze procedures, appetitive scheduled conditioning, and conditioned fear protocols. The distinct brain expression profiles of the VGluT1 and -2 isoforms particularly in telencephalic structures, such as neocortex, hippocampus and striatum, are reflected in very specific behavioral changes. VGluT2(+/-) mice were unimpaired in spatial learning tasks and fear extinction. Conversely, VGluT1(+/-) mice displayed spatial extinction learning deficits and markedly impaired fear extinction. These data indicate that VGluT1, but not VGluT2, plays a role in the neural processes underlying inhibitory learning. Copyright © 2013 Elsevier B.V. All rights reserved.

Fear conditioning and extinction in anxiety- and depression-prone persons.

PubMed

Dibbets, Pauline; van den Broek, Anne; Evers, Elisabeth A T

2015-01-01

Anxiety and depression frequently co-occur and may share similar deficits in the processing of emotional stimuli. High anxiety is associated with a failure in the acquisition and extinction of fear conditioning. Despite the supposed common deficits, no research has been conducted on fear acquisition and extinction in depression. The main aim of the present study was to investigate and compare fear acquisition and extinction in anxiety- and depression-prone participants. Non-clinical anxious, depressive, anxious-depressive and control participants performed a fear discrimination task. During acquisition, the CS+ predicted an aversive event (unconditioned stimulus, US) and the CS- safety (no US). During extinction, the CS+ was no longer followed by the US, rendering it (temporarily) into a safety signal. On each CS participants rated their US expectancy; skin conductance responses (SCRs) were measured throughout. The expectancy scores indicated that high anxiety resulted in less safety learning during acquisition and extinction; no effect of depression was observed. SCRs showed that high-anxiety persons displayed less discrimination learning (CS+ minus CS-) during acquisition than low-anxiety persons. During extinction, high-depression persons demonstrated more discriminative SCR than low-depression persons. The observed discrepancies in response patterns of high-anxiety and -depression persons seem to indicate distinctive information processing of emotional stimuli.

Separation of time-based and trial-based accounts of the partial reinforcement extinction effect.

PubMed

Bouton, Mark E; Woods, Amanda M; Todd, Travis P

2014-01-01

Two appetitive conditioning experiments with rats examined time-based and trial-based accounts of the partial reinforcement extinction effect (PREE). In the PREE, the loss of responding that occurs in extinction is slower when the conditioned stimulus (CS) has been paired with a reinforcer on some of its presentations (partially reinforced) instead of every presentation (continuously reinforced). According to a time-based or "time-accumulation" view (e.g., Gallistel and Gibbon, 2000), the PREE occurs because the organism has learned in partial reinforcement to expect the reinforcer after a larger amount of time has accumulated in the CS over trials. In contrast, according to a trial-based view (e.g., Capaldi, 1967), the PREE occurs because the organism has learned in partial reinforcement to expect the reinforcer after a larger number of CS presentations. Experiment 1 used a procedure that equated partially and continuously reinforced groups on their expected times to reinforcement during conditioning. A PREE was still observed. Experiment 2 then used an extinction procedure that allowed time in the CS and the number of trials to accumulate differentially through extinction. The PREE was still evident when responding was examined as a function of expected time units to the reinforcer, but was eliminated when responding was examined as a function of expected trial units to the reinforcer. There was no evidence that the animal responded according to the ratio of time accumulated during the CS in extinction over the time in the CS expected before the reinforcer. The results thus favor a trial-based account over a time-based account of extinction and the PREE. This article is part of a Special Issue entitled: Associative and Temporal Learning. Copyright © 2013 Elsevier B.V. All rights reserved.

Inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear.

PubMed

Jiang, Lizhu; Mao, Rongrong; Tong, Jianbin; Li, Jinnan; Chai, Anping; Zhou, Qixin; Yang, Yuexiong; Wang, Liping; Li, Lingjiang; Xu, Lin

2016-10-01

Promoting extinction of fear memory is the main treatment of fear disorders, especially post-traumatic stress disorder (PTSD). However, fear extinction is often incomplete in these patients. Our previous study had shown that Rac1 activity in hippocampus plays a crucial role in the learning of contextual fear memory in rats. Here, we further investigated whether Rac1 activity also modulated the extinction of contextual fear memory. We found that massed extinction obviously upregulated hippocampal Rac1 activity and induced long-term extinction of contextual fear in rats. Intrahippocampal injection of the Rac1 inhibitor NSC23766 prevents extinction of contextual fear in massed extinction training rats. In contrast, long-spaced extinction downregulated Rac1 activity and caused less extinction. And Rac1 activator CN04-A promotes extinction of contextual fear in long-spaced extinction rats. Our study demonstrates that inhibition of Rac1 activity in the hippocampus impaired extinction of contextual fear, suggesting that modulating Rac1 activity of the hippocampus may be promising therapy of fear disorders. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sex differences in extinction recall in posttraumatic stress disorder: A pilot fMRI study

PubMed Central

Shvil, Erel; Sullivan, Gregory M.; Schafer, Scott; Markowitz, John C.; Campeas, Miriam; Wager, Tor D.; Milad, Mohammed R.; Neria, Yuval

2014-01-01

Recent research has found that individuals with posttraumatic stress disorder (PTSD) exhibit an impaired memory of fear extinction compounded by deficient functional activation of key nodes of the fear network including the amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC). Research has shown these regions are sexually dimorphic and activate differentially in healthy men and women during fear learning tasks. To explore biological markers of sex differences following exposure to psychological trauma, we used a fear learning and extinction paradigm together with functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) to assess 31 individuals with PTSD (18 women; 13 men) and 25 matched trauma-exposed healthy control subjects (13 women; 12 men). Whereas no sex differences appeared within the trauma-exposed healthy control group, both psychophysiological and neural activation patterns within the PTSD group indicated deficient recall of extinction memory among men and not among women. Men with PTSD exhibited increased activation in the left rostral dACC during extinction recall compared with women with PTSD. These findings highlight the importance of tracking sex differences in fear extinction when characterizing the underlying neurobiological mechanisms of PTSD psychopathology. PMID:24560771

Auditory peripersonal space in humans.

PubMed

Farnè, Alessandro; Làdavas, Elisabetta

2002-10-01

In the present study we report neuropsychological evidence of the existence of an auditory peripersonal space representation around the head in humans and its characteristics. In a group of right brain-damaged patients with tactile extinction, we found that a sound delivered near the ipsilesional side of the head (20 cm) strongly extinguished a tactile stimulus delivered to the contralesional side of the head (cross-modal auditory-tactile extinction). By contrast, when an auditory stimulus was presented far from the head (70 cm), cross-modal extinction was dramatically reduced. This spatially specific cross-modal extinction was most consistently found (i.e., both in the front and back spaces) when a complex sound was presented, like a white noise burst. Pure tones produced spatially specific cross-modal extinction when presented in the back space, but not in the front space. In addition, the most severe cross-modal extinction emerged when sounds came from behind the head, thus showing that the back space is more sensitive than the front space to the sensory interaction of auditory-tactile inputs. Finally, when cross-modal effects were investigated by reversing the spatial arrangement of cross-modal stimuli (i.e., touch on the right and sound on the left), we found that an ipsilesional tactile stimulus, although inducing a small amount of cross-modal tactile-auditory extinction, did not produce any spatial-specific effect. Therefore, the selective aspects of cross-modal interaction found near the head cannot be explained by a competition between a damaged left spatial representation and an intact right spatial representation. Thus, consistent with neurophysiological evidence from monkeys, our findings strongly support the existence, in humans, of an integrated cross-modal system coding auditory and tactile stimuli near the body, that is, in the peripersonal space.

Dopamine and extinction: A convergence of theory with fear and reward circuitry

PubMed Central

Abraham, Antony D.; Neve, Kim A.; Lattal, K. Matthew

2014-01-01

Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine’s function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. PMID:24269353

Dopamine and extinction: a convergence of theory with fear and reward circuitry.

PubMed

Abraham, Antony D; Neve, Kim A; Lattal, K Matthew

2014-02-01

Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. Copyright © 2013 Elsevier Inc. All rights reserved.

Fear Conditioning in an Abdominal Pain Model: Neural Responses during Associative Learning and Extinction in Healthy Subjects

PubMed Central

Kattoor, Joswin; Gizewski, Elke R.; Kotsis, Vassilios; Benson, Sven; Gramsch, Carolin; Theysohn, Nina; Maderwald, Stefan; Forsting, Michael; Schedlowski, Manfred; Elsenbruch, Sigrid

2013-01-01

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement. In N = 21 healthy humans, visual conditioned stimuli (CS+) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS−) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness. Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS+. During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS− was observed. In the reinstatement phase, a tendency for parahippocampal activation was found. Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain. PMID:23468832

Orexin/hypocretin receptor 1 signaling mediates Pavlovian cue-food conditioning and extinction.

PubMed

Keefer, Sara E; Cole, Sindy; Petrovich, Gorica D

2016-08-01

Learned food cues can drive feeding in the absence of hunger, and orexin/hypocretin signaling is necessary for this type of overeating. The current study examined whether orexin also mediates cue-food learning during the acquisition and extinction of these associations. In Experiment 1, rats underwent two sessions of Pavlovian appetitive conditioning, consisting of tone-food presentations. Prior to each session, rats received either the orexin 1 receptor antagonist SB-334867 (SB) or vehicle systemically. SB treatment did not affect conditioned responses during the first conditioning session, measured as food cup behavior during the tone and latency to approach the food cup after the tone onset, compared to the vehicle group. During the second conditioning session, SB treatment attenuated learning. All groups that received SB, prior to either the first or second conditioning session, displayed significantly less food cup behavior and had longer latencies to approach the food cup after tone onset compared to the vehicle group. These findings suggest orexin signaling at the 1 receptor mediates the consolidation and recall of cue-food acquisition. In Experiment 2, another group of rats underwent tone-food conditioning sessions (drug free), followed by two extinction sessions under either SB or vehicle treatment. Similar to Experiment 1, SB did not affect conditioned responses during the first session. During the second extinction session, the group that received SB prior to the first extinction session, but vehicle prior to the second, expressed conditioned food cup responses longer after tone offset, when the pellets were previously delivered during conditioning, and maintained shorter latencies to approach the food cup compared to the other groups. The persistence of these conditioned behaviors indicates impairment in extinction consolidation due to SB treatment during the first extinction session. Together, these results demonstrate an important role for orexin signaling during Pavlovian appetitive conditioning and extinction. Copyright © 2016 Elsevier Inc. All rights reserved.

Orexin/hypocretin receptor 1 signaling mediates Pavlovian cue-food conditioning and extinction

PubMed Central

Keefer, Sara E.; Cole, Sindy; Petrovich, Gorica D.

2016-01-01

Learned food cues can drive feeding in the absence of hunger, and orexin/hypocretin signaling is necessary for this type of overeating. The current study examined whether orexin also mediates cue-food learning during the acquisition and extinction of these associations. In Experiment 1, rats underwent two sessions of Pavlovian appetitive conditioning, consisting of tone-food presentations. Prior to each session, rats received either the orexin 1 receptor antagonist SB-334867 (SB) or vehicle systemically. SB treatment did not affect conditioned responses during the first conditioning session, measured as food cup behavior during the tone and latency to approach the food cup after the tone onset, compared to the vehicle group. During the second conditioning session, SB treatment attenuated learning. All groups that received SB, prior to either the first or second conditioning session, displayed significantly less food cup behavior and had longer latencies to approach the food cup after tone onset compared to the vehicle group. These findings suggest orexin signaling at the 1 receptor mediates the consolidation and recall of cue-food acquisition. In Experiment 2, another group of rats underwent tone-food conditioning sessions (drug free), followed by two extinction sessions under either SB or vehicle treatment. Similar to Experiment 1, SB did not affect conditioned responses during the first session. During the second extinction session, the group that received SB prior to the first extinction session, but vehicle prior to the second, expressed conditioned food cup responses longer after tone offset, when the pellets were previously delivered during conditioning, and maintained shorter latencies to approach the food cup compared to the other groups. The persistence of these conditioned behaviors indicates impairment in extinction consolidation due to SB treatment during the first extinction session. Together, these results demonstrate an important role for orexin signaling during Pavlovian appetitive conditioning and extinction. PMID:26945612

D-cycloserine Deters Reacquisition of Cocaine Self-Administration by Augmenting Extinction Learning

PubMed Central

Nic Dhonnchadha, Bríd Á; Szalay, Jonathan J; Achat-Mendes, Cindy; Platt, Donna M; Otto, Michael W; Spealman, Roger D; Kantak, Kathleen M

2010-01-01

Augmentation of cue exposure (extinction) therapy with cognitive-enhancing pharmacotherapy may offer an effective strategy to combat cocaine relapse. To investigate this possibility at the preclinical level, rats and squirrel monkeys were trained to self-administer cocaine paired with a brief visual cue. Lever pressing was subsequently extinguished by withholding cocaine injections while maintaining response-contingent presentations of the cue. The glycine partial agonist D-cycloserine (DCS; 15 and 30 mg/kg in rats, 3 and 10 mg/kg in monkeys) was evaluated for its effects on the rate of extinction and subsequent reacquisition of cocaine self-administration. Compared with vehicle, pretreatment with 30 mg/kg DCS 0.5 h before extinction training reduced the number of responses and latency to reach the extinction criterion in rats, but neither dose of DCS altered these measures in monkeys. In both species, pretreatment with the higher dose of DCS before extinction training significantly attenuated reacquisition of cocaine self-administration compared with either extinction training in the absence of DCS or DCS in the absence of explicit extinction. Furthermore, treatment with 30 mg/kg DCS accompanied by brief handling (a stress induction) immediately after but not 6 h after extinction training attenuated reacquisition of cocaine self-administration in rats. No adverse effects of 10 mg/kg DCS were evident in quantitative observational studies in monkeys. The results suggest that DCS augmented consolidation of extinction learning to deter reacquisition of cocaine self-administration in rats and monkeys. The results suggest that DCS combined with exposure therapy may constitute a rational strategy for the clinical management of cocaine relapse. PMID:19741593

Deficits in the extinction of ethanol-seeking behavior following chronic intermittent ethanol exposure are attenuated with positive allosteric modulation of mGlu5.

PubMed

Gass, J T; McGonigal, J T; Chandler, L J

2017-02-01

Alcoholism is a chronic relapsing disorder characterized by periods of heavy alcohol consumption and unsuccessful attempts at abstinence. Relapse is one of the most problematic aspects in the treatment of alcoholism and is triggered by ethanol-associated cues. Extinction-based cue exposure therapies have proven ineffective in the treatment of alcoholism. However, positive allosteric modulation of mGlu5 with CDPPB enhances the extinction learning of alcohol-seeking behavior. The current study investigated the impact of chronic alcohol exposure on the extinction of ethanol-seeking behavior. Adult Wistar rats were trained to self-administer alcohol with a light/tone stimulus serving as the alcohol cue. After training, one group of rats was exposed to chronic intermittent ethanol (CIE) daily for a period of 2 weeks to induce ethanol dependence. Control rats were exposed to air for the same period of time. Both groups were then retrained to self-administer ethanol and subsequently tested for changes in extinction learning. CIE exposed rats consumed more ethanol compared to their pre-CIE levels and to control rats. During extinction training, CIE rats responded significantly more on the previously active lever and required more sessions to reach extinction criteria compared to control rats. Treatment with CDPPB facilitated extinction in control rats and attenuated the increased resistance to extinction in CIE-exposed rats. These results demonstrate that chronic ethanol exposure not only alters ethanol intake, but also the extinction of ethanol-seeking behaviors. The ability to attenuate deficits through modulation of mGlu5 provides a potential target for pharmacological manipulation that could ultimately reduce relapse in alcoholics. Copyright © 2016 Elsevier Ltd. All rights reserved.

PI3-kinase cascade has a differential role in acquisition and extinction of conditioned fear memory in juvenile and adult rats.

PubMed

Slouzkey, Ilana; Maroun, Mouna

2016-12-01

The basolateral amygdala (BLA), medial prefrontal cortex (mPFC) circuit, plays a crucial role in acquisition and extinction of fear memory. Extinction of aversive memories is mediated, at least in part, by the phosphoinositide-3 kinase (PI3K)/Akt pathway in adult rats. There is recent interest in the neural mechanisms that mediate fear and extinction in juvenile animals and whether these mechanisms are distinctive from those in adult animals. In the present study, we examined (1) changes in phosphorylation of Akt in the BLA and mPFC after fear conditioning and extinction in juvenile and adult rats and (2) the effect of BLA and mPFC localized inhibition of the PI3K following acquisition and extinction of contextual fear memory. Our results show that Akt phosphorylation is increased following acquisition of contextual fear learning in the BLA but not in the mPFC in adult and juvenile rats. Extinction learning was not associated with changes in Akt phosphorylation. Although there were no differences in the pattern of phosphorylation of Akt either in adult or juvenile rats, microinjection of the PI3K inhibitor, LY294002, into the BLA or mPFC elicited differential effects on fear memory acquisition and extinction, depending on the site and timing of the microinjection, as well as on the age of the animal. These results suggest that PI3K/Akt has a differential role in formation, retrieval, and extinction of contextual fear memory in juvenile and adult animals, and point to developmental differences between adult and juvenile rats in mechanisms of extinction. © 2016 Slouzkey and Maroun; Published by Cold Spring Harbor Laboratory Press.

Estimating extinction using unsupervised machine learning

NASA Astrophysics Data System (ADS)

Meingast, Stefan; Lombardi, Marco; Alves, João

2017-05-01

Dust extinction is the most robust tracer of the gas distribution in the interstellar medium, but measuring extinction is limited by the systematic uncertainties involved in estimating the intrinsic colors to background stars. In this paper we present a new technique, Pnicer, that estimates intrinsic colors and extinction for individual stars using unsupervised machine learning algorithms. This new method aims to be free from any priors with respect to the column density and intrinsic color distribution. It is applicable to any combination of parameters and works in arbitrary numbers of dimensions. Furthermore, it is not restricted to color space. Extinction toward single sources is determined by fitting Gaussian mixture models along the extinction vector to (extinction-free) control field observations. In this way it becomes possible to describe the extinction for observed sources with probability densities, rather than a single value. Pnicer effectively eliminates known biases found in similar methods and outperforms them in cases of deep observational data where the number of background galaxies is significant, or when a large number of parameters is used to break degeneracies in the intrinsic color distributions. This new method remains computationally competitive, making it possible to correctly de-redden millions of sources within a matter of seconds. With the ever-increasing number of large-scale high-sensitivity imaging surveys, Pnicer offers a fast and reliable way to efficiently calculate extinction for arbitrary parameter combinations without prior information on source characteristics. The Pnicer software package also offers access to the well-established Nicer technique in a simple unified interface and is capable of building extinction maps including the Nicest correction for cloud substructure. Pnicer is offered to the community as an open-source software solution and is entirely written in Python.

Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats

PubMed Central

Cruz, Emmanuel; Soler-Cedeño, Omar; Negrón, Geovanny; Criado-Marrero, Marangelie; Chompré, Gladys

2015-01-01

Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase. PMID:26354908

Amygdala-ventral striatum circuit activation decreases long-term fear

PubMed Central

Correia, Susana S; McGrath, Anna G; Lee, Allison; Graybiel, Ann M; Goosens, Ki A

2016-01-01

In humans, activation of the ventral striatum, a region associated with reward processing, is associated with the extinction of fear, a goal in the treatment of fear-related disorders. This evidence suggests that extinction of aversive memories engages reward-related circuits, but a causal relationship between activity in a reward circuit and fear extinction has not been demonstrated. Here, we identify a basolateral amygdala (BLA)-ventral striatum (NAc) pathway that is activated by extinction training. Enhanced recruitment of this circuit during extinction learning, either by pairing reward with fear extinction training or by optogenetic stimulation of this circuit during fear extinction, reduces the return of fear that normally follows extinction training. Our findings thus identify a specific BLA-NAc reward circuit that can regulate the persistence of fear extinction and point toward a potential therapeutic target for disorders in which the return of fear following extinction therapy is an obstacle to treatment. DOI: http://dx.doi.org/10.7554/eLife.12669.001 PMID:27671733

Bilateral Alternating Auditory Stimulations Facilitate Fear Extinction and Retrieval.

PubMed

Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie

2017-01-01

Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR.

Bilateral Alternating Auditory Stimulations Facilitate Fear Extinction and Retrieval

PubMed Central

Boukezzi, Sarah; Silva, Catarina; Nazarian, Bruno; Rousseau, Pierre-François; Guedj, Eric; Valenzuela-Moguillansky, Camila; Khalfa, Stéphanie

2017-01-01

Disruption of fear conditioning, its extinction and its retrieval are at the core of posttraumatic stress disorder (PTSD). Such deficits, especially fear extinction delay, disappear after alternating bilateral stimulations (BLS) during eye movement desensitization and reprocessing (EMDR) therapy. An animal model of fear recovery, based on auditory cued fear conditioning and extinction learning, recently showed that BLS facilitate fear extinction and fear extinction retrieval. Our goal was to determine if these previous results found in animals can be reproduced in humans. Twenty-two healthy participants took part in a classical fear conditioning, extinction, and extinction recall paradigm. Behavioral responses (fear expectations) as well as psychophysiological measures (skin conductance responses, SCRs) were recorded. The results showed a significant fear expectation decrease during fear extinction with BLS. Additionally, SCR for fear extinction retrieval were significantly lower with BLS. Our results demonstrate the importance of BLS to reduce negative emotions, and provide a successful model to further explore the neural mechanisms underlying the sole BLS effect in the EMDR. PMID:28659851

Hippocampal Context Processing during Acquisition of a Predictive Learning Task Is Associated with Renewal in Extinction Recall.

PubMed

Lissek, Silke; Glaubitz, Benjamin; Schmidt-Wilcke, Tobias; Tegenthoff, Martin

2016-05-01

Renewal is defined as the recovery of an extinguished response if extinction and retrieval contexts differ. The context dependency of extinction, as demonstrated by renewal, has important implications for extinction-based therapies. Persons showing renewal (REN) exhibit higher hippocampal activation during extinction in associative learning than those without renewal (NOREN), demonstrating hippocampal context processing, and recruit ventromedial pFC in retrieval. Apart from these findings, brain processes generating renewal remain largely unknown. Conceivably, processing differences in task-relevant brain regions that ultimately lead to renewal may occur already in initial acquisition of associations. Therefore, in two fMRI studies, we investigated overall brain activation and hippocampal activation in REN and NOREN during acquisition of an associative learning task in response to presentation of a context alone or combined with a cue. Results of two studies demonstrated significant activation differences between the groups: In Study 1, a support vector machine classifier correctly assigned participants' brain activation patterns to REN and NOREN groups, respectively. In Study 2, REN and NOREN showed similar hippocampal involvement during context-only presentation, suggesting processing of novelty, whereas overall hippocampal activation to the context-cue compound, suggesting compound encoding, was higher in REN. Positive correlations between hippocampal activation and renewal level indicated more prominent hippocampal processing in REN. Results suggest that hippocampal processing of the context-cue compound rather than of context only during initial learning is related to a subsequent renewal effect. Presumably, REN participants use distinct encoding strategies during acquisition of context-related tasks, which reflect in their brain activation patterns and contribute to a renewal effect.

Environmental enrichment facilitates cocaine-cue extinction, deters reacquisition of cocaine self-administration and alters AMPAR GluA1 expression and phosphorylation.

PubMed

Gauthier, Jamie M; Lin, Amy; Nic Dhonnchadha, Bríd Á; Spealman, Roger D; Man, Heng-Ye; Kantak, Kathleen M

2017-01-01

This study investigated the combination of environmental enrichment (EE) with cocaine-cue extinction training on reacquisition of cocaine self-administration. Rats were trained under a second-order schedule for which responses were maintained by cocaine injections and cocaine-paired stimuli. During three weekly extinction sessions, saline was substituted for cocaine but cocaine-paired stimuli were presented. Rats received 4-h periods of EE at strategic time points during extinction training, or received NoEE. Additional control rats received EE or NoEE without extinction training. One week later, reacquisition of cocaine self-administration was evaluated for 15 sessions, and then GluA1 expression, a cellular substrate for learning and memory, was measured in selected brain regions. EE provided both 24 h before and immediately after extinction training facilitated extinction learning and deterred reacquisition of cocaine self-administration for up to 13 sessions. Each intervention by itself (EE alone or extinction alone) was ineffective, as was EE scheduled at individual time points (EE 4 h or 24 h before, or EE immediately or 6 h after, each extinction training session). Under these conditions, rats rapidly reacquired baseline rates of cocaine self-administration. Cocaine self-administration alone decreased total GluA1 and/or pSer845GluA1 expression in basolateral amygdala and nucleus accumbens. Extinction training, with or without EE, opposed these changes and also increased total GluA1 in ventromedial prefrontal cortex and dorsal hippocampus. EE alone increased pSer845GluA1 and EE combined with extinction training decreased pSer845GluA1 in ventromedial prefrontal cortex. EE might be a useful adjunct to extinction therapy by enabling neuroplasticity that deters relapse to cocaine self-administration. © 2015 Society for the Study of Addiction.

The Small GTPase Rac1 Contributes to Extinction of Aversive Memories of Drug Withdrawal by Facilitating GABAA Receptor Endocytosis in the vmPFC.

PubMed

Wang, Weisheng; Ju, Yun-Yue; Zhou, Qi-Xin; Tang, Jian-Xin; Li, Meng; Zhang, Lei; Kang, Shuo; Chen, Zhong-Guo; Wang, Yu-Jun; Ji, Hui; Ding, Yu-Qiang; Xu, Lin; Liu, Jing-Gen

2017-07-26

Extinction of aversive memories has been a major concern in neuropsychiatric disorders, such as anxiety disorders and drug addiction. However, the mechanisms underlying extinction of aversive memories are not fully understood. Here, we report that extinction of conditioned place aversion (CPA) to naloxone-precipitated opiate withdrawal in male rats activates Rho GTPase Rac1 in the ventromedial prefrontal cortex (vmPFC) in a BDNF-dependent manner, which determines GABA A receptor (GABA A R) endocytosis via triggering synaptic translocation of activity-regulated cytoskeleton-associated protein (Arc) through facilitating actin polymerization. Active Rac1 is essential and sufficient for GABA A R endocytosis and CPA extinction. Knockdown of Rac1 expression within the vmPFC of rats using Rac1-shRNA suppressed GABA A R endocytosis and CPA extinction, whereas expression of a constitutively active form of Rac1 accelerated GABA A R endocytosis and CPA extinction. The crucial role of GABA A R endocytosis in the LTP induction and CPA extinction is evinced by the findings that blockade of GABA A R endocytosis by a dynamin function-blocking peptide (Myr-P4) abolishes LTP induction and CPA extinction. Thus, the present study provides first evidence that Rac1-dependent GABA A R endocytosis plays a crucial role in extinction of aversive memories and reveals the sequence of molecular events that contribute to learning experience modulation of synaptic GABA A R endocytosis. SIGNIFICANCE STATEMENT This study reveals that Rac1-dependent GABA A R endocytosis plays a crucial role in extinction of aversive memories associated with drug withdrawal and identifies Arc as a downstream effector of Rac1 regulations of synaptic plasticity as well as learning and memory, thereby suggesting therapeutic targets to promote extinction of the unwanted memories. Copyright © 2017 the authors 0270-6474/17/377096-15$15.00/0.

BDNFval66met affects neural activation pattern during fear conditioning and 24 h delayed fear recall.

PubMed

Lonsdorf, Tina B; Golkar, Armita; Lindström, Kara M; Haaker, Jan; Öhman, Arne; Schalling, Martin; Ingvar, Martin

2015-05-01

Brain-derived neurotrophic factor (BDNF), the most abundant neutrophin in the mammalian central nervous system, is critically involved in synaptic plasticity. In both rodents and humans, BDNF has been implicated in hippocampus- and amygdala-dependent learning and memory and has more recently been linked to fear extinction processes. Fifty-nine healthy participants, genotyped for the functional BDNFval66met polymorphism, underwent a fear conditioning and 24h-delayed extinction protocol while skin conductance and blood oxygenation level dependent (BOLD) responses (functional magnetic resonance imaging) were acquired. We present the first report of neural activation pattern during fear acquisition 'and' extinction for the BDNFval66met polymorphism using a differential conditioned stimulus (CS)+ > CS- comparison. During conditioning, we observed heightened allele dose-dependent responses in the amygdala and reduced responses in the subgenual anterior cingulate cortex in BDNFval66met met-carriers. During early extinction, 24h later, we again observed heightened responses in several regions ascribed to the fear network in met-carriers as opposed to val-carriers (insula, amygdala, hippocampus), which likely reflects fear memory recall. No differences were observed during late extinction, which likely reflects learned extinction. Our data thus support previous associations of the BDNFval66met polymorphism with neural activation in the fear and extinction network, but speak against a specific association with fear extinction processes. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation

PubMed Central

Kutlu, Munir Gunes; Oliver, Chicora; Huang, Peng; Liu-Chen, Lee-Yuan; Gould, Thomas J.

2017-01-01

Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder. PMID:27378334

D-Cycloserine Does Not Facilitate Fear Extinction by Reducing Conditioned Stimulus Processing or Promoting Conditioned Inhibition to Contextual Cues

ERIC Educational Resources Information Center

Baker, Kathryn D.; McNally, Gavan P.; Richardson, Rick

2012-01-01

The NMDA receptor partial agonist d-cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions…

Reorganization of Learning-Associated Prefrontal Synaptic Plasticity between the Recall of Recent and Remote Fear Extinction Memory

ERIC Educational Resources Information Center

Hugues, Sandrine; Garcia, Rene

2007-01-01

We have previously shown that fear extinction is accompanied by an increase of synaptic efficacy in inputs from the ventral hippocampus (vHPC) and mediodorsal thalamus (MD) to the medial prefrontal cortex (mPFC) and that disrupting these changes to mPFC synaptic transmission compromises extinction processes. The aim of this study was to examine…

Enhanced extinction of contextual fear conditioning in ClockΔ19 mutant mice.

PubMed

Bernardi, Rick E; Spanagel, Rainer

2014-08-01

Clock genes have been implicated in several disorders, such as schizophrenia, bipolar disorder, autism spectrum disorders, and drug dependence. However, few studies to date have examined the role of clock genes in fear-related behaviors. The authors used mice with the ClockΔ19 mutation to assess the involvement of this gene in contextual fear conditioning. Male wild-type (WT) and ClockΔ19 mutant mice underwent a single session of contextual fear conditioning (12 min, 4 unsignaled shocks), followed by daily 12-min retention trials. There were no differences between mutant and WT mice in the acquisition of contextual fear, and WT and mutant mice demonstrated similar freezing during the first retention session. However, extinction of contextual fear was accelerated in mutant mice across the remaining retention sessions, as compared to WT mice, suggesting a role for Clock in extinction following aversive learning. Because the ClockΔ19 mutation has previously been demonstrated to result in an increase in dopamine signaling, the authors confirmed the role of dopamine in extinction learning using preretention session administration of a low dose of the dopamine transport reuptake inhibitor modafinil (0.75 mg/kg), which resulted in decreased freezing across retention sessions. These findings are consistent with an emerging portrayal of the importance of Clock genes in noncircadian functions, as well as the important role of dopamine in extinction learning.

A Mismatch-Based Model for Memory Reconsolidation and Extinction in Attractor Networks

PubMed Central

Amaral, Olavo B.

2011-01-01

The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation. PMID:21826231

Increased perceived self-efficacy facilitates the extinction of fear in healthy participants

PubMed Central

Zlomuzica, Armin; Preusser, Friederike; Schneider, Silvia; Margraf, Jürgen

2015-01-01

Self-efficacy has been proposed as an important element of a successful cognitive behavioral treatment (CBT). Positive changes in perceived self-efficacy have been linked to an improved adaptive emotional and behavioral responding in the context of anxiety-provoking situations. Furthermore, a positive influence of increased self-efficacy on cognitive functions has been confirmed. The present study examined the effect of verbal persuasion on perceived self-efficacy and fear extinction. Healthy participants were subjected to a standardized differential fear conditioning paradigm. After fear acquisition, half of the participants received a verbal persuasion aimed at increasing perceived self-efficacy. The extinction of fear was assessed immediately thereafter on both the implicit and explicit level. Our results suggest that an increased perceived self-efficacy was associated with enhanced extinction, evidenced on the psychophysiological level and accompanied by more pronounced decrements in conditioned negative valence. Changes in extinction were not due to a decrease in overall emotional reactivity to conditioned stimuli (CS). In addition, debriefing participants about the false positive feedback did not affect the processing of already extinguished conditioned responses during a subsequent continued extinction phase. Our results suggest that positive changes in perceived self-efficacy can be beneficial for emotional learning. Findings are discussed with respect to strategies aimed at increasing extinction learning in the course of exposure-based treatments. PMID:26528152

Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network.

PubMed

Childs, Jessica E; DeLeon, Jaime; Nickel, Emily; Kroener, Sven

2017-01-01

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug- and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects. © 2016 Childs et al.; Published by Cold Spring Harbor Laboratory Press.

Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network

PubMed Central

Childs, Jessica E.; DeLeon, Jaime; Nickel, Emily

2017-01-01

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic plasticity to facilitate extinction of appetitive behaviors and to reduce relapse. Rats self-administered cocaine and were given VNS during extinction. Relapse to drug-seeking was assessed in a cued reinstatement session. We used immunohistochemistry to measure changes in the expression of the phosphorylated transcription factor cAMP response-element binding protein (pCREB) in the PFC and the basolateral amygdala (BLA), which regulate cue learning and extinction. In vivo recordings of evoked field potentials measured drug- and VNS-induced changes in metaplasticity in the pathway from the PFC to the BLA. VNS-treated rats showed improved rates of extinction and reduced reinstatement. Following reinstatement, pCREB levels were reduced in the IL and BLA of VNS-treated rats. Evoked responses in the BLA were greatly reduced in VNS-treated rats, and these rats were also resistant to the induction of LTD. Taken together, these results show that VNS facilitates extinction and reduces reinstatement. Changes in the pathway between the PFC and the amygdala may contribute to these beneficial effects. PMID:27980074

The inhibition of acquired fear.

PubMed

Izquierdo, Iván; Cammarota, Martín; Vianna, Mónica M R; Bevilaqua, Lía R M

2004-01-01

A conditioned stimulus (CS) associated with a fearsome unconditioned stimulus (US) generates learned fear. Acquired fear is at the root of a variety of mental disorders, among which phobias, generalized anxiety, the posttraumatic stress disorder (PTSD) and some forms of depression. The simplest way to inhibit learned fear is to extinguish it, which is usually done by repeatedly presenting the CS alone, so that a new association, CS-"no US", will eventually overcome the previously acquired CS-US association. Extinction was first described by Pavlov as a form of "internal inhibition" and was recommended by Freud and Ferenczi in the 1920s (who called it "habituation") as the treatment of choice for phobic disorders. It is used with success till this day, often in association with anxiolytic drugs. Extinction has since then been applied, also successfully and also often in association with anxiolytics, to the treatment of panic, generalized anxiety disorders and, more recently, PTSD. Extinction of learned fear involves gene expression, protein synthesis, N-methyl-D-aspartate (NMDA) receptors and signaling pathways in the hippocampus and the amygdala at the time of the first CS-no US association. It can be enhanced by increasing the exposure to the "no US" component at the time of behavioral testing, to the point of causing the complete uninstallment of the original fear response. Some theorists have recently proposed that reiteration of the CS alone may induce a reconsolidation of the learned behavior instead of its extinction. Reconsolidation would preserve the original memory from the labilization induced by its retrieval. If true, this would of course be disastrous for the psychotherapy of fear-motivated disorders. Here we show that neither the CS nor retrieval cause anything remotely like reconsolidation, but just extinction. In fact, our findings indicate that the reconsolidation hypothesis is essentially incorrect, at least for the form of contextual fear most commonly studied in rodents. Therefore, it seems safe to continue using extinction-based forms of therapy for disorders secondary to acquired fear. Further, it is useful and desirable to device procedures by which the "no US" component of the extinction is strengthened in order to alleviate the symptoms of victims of acquired fear.

Treatment of avoidance behavior as an adjunct to exposure therapy: Insights from modern learning theory.

PubMed

Treanor, Michael; Barry, Tom J

2017-09-01

Pathological avoidance of benign stimuli is a hallmark of anxiety and related disorders, and exposure-based treatments have often encouraged the removal of avoidance, or safety behaviors, due to their negative effects on extinction learning. Unfortunately, empirical evidence suggests that avoidance behaviors can persist following treatment, and the mere availability of avoidance behavior can be sufficient to renew fear following successful extinction learning. The present paper critically examines the function of avoidance behavior through the lens of modern learning theory, and speculates on novel behavioral and pharmacological strategies for targeting avoidance as an adjunct to current evidence-based treatments. Copyright © 2017. Published by Elsevier Ltd.

Enhancement of Extinction Learning Attenuates Ethanol-Seeking Behavior and Alters Plasticity in the Prefrontal Cortex

PubMed Central

Trantham-Davidson, Heather; Kassab, Amanda S.; Glen, William B.; Olive, M. Foster; Chandler, L. Judson

2014-01-01

Addiction is a chronic relapsing disorder in which relapse is often initiated by exposure to drug-related cues. The present study examined the effects of mGluR5 activation on extinction of ethanol-cue-maintained responding, relapse-like behavior, and neuronal plasticity. Rats were trained to self-administer ethanol and then exposed to extinction training during which they were administered either vehicle or the mGluR5 positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) or CDPPB. CDPPB treatment reduced active lever responding during extinction, decreased the total number of extinction sessions required to meet criteria, and attenuated cue-induced reinstatement of ethanol seeking. CDPPB facilitation of extinction was blocked by the local infusion of the mGluR5 antagonist 3-((2-methyl-4-thiazolyl)ethynyl) pyridine into the infralimbic (IfL) cortex, but had no effect when infused into the prelimbic (PrL) cortex. Analysis of dendritic spines revealed alterations in structural plasticity, whereas electrophysiological recordings demonstrated differential alterations in glutamatergic neurotransmission in the PrL and IfL cortex. Extinction was associated with increased amplitude of evoked synaptic PrL and IfL NMDA currents but reduced amplitude of PrL AMPA currents. Treatment with CDPPB prevented the extinction-induced enhancement of NMDA currents in PrL without affecting NMDA currents in the IfL. Whereas CDPPB treatment did not alter the amplitude of PrL or IfL AMPA currents, it did promote the expression of IfL calcium-permeable GluR2-lacking receptors in both abstinence- and extinction-trained rats, but had no effect in ethanol-naive rats. These results confirm changes in the PrL and IfL cortex in glutamatergic neurotransmission during extinction learning and demonstrate that manipulation of mGluR5 facilitates extinction of ethanol cues in association with neuronal plasticity. PMID:24872560

Enhancement of extinction learning attenuates ethanol-seeking behavior and alters plasticity in the prefrontal cortex.

PubMed

Gass, Justin T; Trantham-Davidson, Heather; Kassab, Amanda S; Glen, William B; Olive, M Foster; Chandler, L Judson

2014-05-28

Addiction is a chronic relapsing disorder in which relapse is often initiated by exposure to drug-related cues. The present study examined the effects of mGluR5 activation on extinction of ethanol-cue-maintained responding, relapse-like behavior, and neuronal plasticity. Rats were trained to self-administer ethanol and then exposed to extinction training during which they were administered either vehicle or the mGluR5 positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) or CDPPB. CDPPB treatment reduced active lever responding during extinction, decreased the total number of extinction sessions required to meet criteria, and attenuated cue-induced reinstatement of ethanol seeking. CDPPB facilitation of extinction was blocked by the local infusion of the mGluR5 antagonist 3-((2-methyl-4-thiazolyl)ethynyl) pyridine into the infralimbic (IfL) cortex, but had no effect when infused into the prelimbic (PrL) cortex. Analysis of dendritic spines revealed alterations in structural plasticity, whereas electrophysiological recordings demonstrated differential alterations in glutamatergic neurotransmission in the PrL and IfL cortex. Extinction was associated with increased amplitude of evoked synaptic PrL and IfL NMDA currents but reduced amplitude of PrL AMPA currents. Treatment with CDPPB prevented the extinction-induced enhancement of NMDA currents in PrL without affecting NMDA currents in the IfL. Whereas CDPPB treatment did not alter the amplitude of PrL or IfL AMPA currents, it did promote the expression of IfL calcium-permeable GluR2-lacking receptors in both abstinence- and extinction-trained rats, but had no effect in ethanol-naive rats. These results confirm changes in the PrL and IfL cortex in glutamatergic neurotransmission during extinction learning and demonstrate that manipulation of mGluR5 facilitates extinction of ethanol cues in association with neuronal plasticity. Copyright © 2014 the authors 0270-6474/14/347562-13$15.00/0.

The L-Type Voltage-Gated Calcium Channel Ca [subscript V] 1.2 Mediates Fear Extinction and Modulates Synaptic Tone in the Lateral Amygdala

ERIC Educational Resources Information Center

Temme, Stephanie J.; Murphy, Geoffrey G.

2017-01-01

L-type voltage-gated calcium channels (LVGCCs) have been implicated in both the formation and the reduction of fear through Pavlovian fear conditioning and extinction. Despite the implication of LVGCCs in fear learning and extinction, studies of the individual LVGCC subtypes, Ca[subscript V]1.2 and Ca[subscript V] 1.3, using transgenic mice have…

Hormonal Regulation of Extinction: Implication for Mechanisms of Gender Difference in PTSD

DTIC Science & Technology

2009-09-01

role of gonadal hormones in the regulation of Pavlovian fear conditioning and its extinction. Pavlovian fear conditioning and its extinction serve...learning in Pavlovian fear conditioning involves training with the presentation of an innocuous stimulus (the conditioned stimulus – CS) that is associated...GD, Schlinger BA, Fanselow MS (1998) Testicular hormones do not regulate sexually dimorphic Pavlovian fear conditioning or perforant- path long-term

Sex differences in extinction recall in posttraumatic stress disorder: a pilot fMRI study.

PubMed

Shvil, Erel; Sullivan, Gregory M; Schafer, Scott; Markowitz, John C; Campeas, Miriam; Wager, Tor D; Milad, Mohammed R; Neria, Yuval

2014-09-01

Recent research has found that individuals with posttraumatic stress disorder (PTSD) exhibit an impaired memory of fear extinction compounded by deficient functional activation of key nodes of the fear network including the amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (dACC). Research has shown these regions are sexually dimorphic and activate differentially in healthy men and women during fear learning tasks. To explore biological markers of sex differences following exposure to psychological trauma, we used a fear learning and extinction paradigm together with functional magnetic resonance imaging (fMRI) and skin conductance response (SCR) to assess 31 individuals with PTSD (18 women; 13 men) and 25 matched trauma-exposed healthy control subjects (13 women; 12 men). Whereas no sex differences appeared within the trauma-exposed healthy control group, both psychophysiological and neural activation patterns within the PTSD group indicated deficient recall of extinction memory among men and not among women. Men with PTSD exhibited increased activation in the left rostral dACC during extinction recall compared with women with PTSD. These findings highlight the importance of tracking sex differences in fear extinction when characterizing the underlying neurobiological mechanisms of PTSD psychopathology. Copyright © 2014 Elsevier Inc. All rights reserved.

Impaired Formation of Stimulus–Response, But Not Action–Outcome, Associations in Rats with Methamphetamine-Induced Neurotoxicity

PubMed Central

Son, Jong-Hyun; Latimer, Christine; Keefe, Kristen A

2011-01-01

Methamphetamine (METH) induces neurotoxic changes, including partial striatal dopamine depletions, which are thought to contribute to cognitive dysfunction in rodents and humans. The dorsal striatum is implicated in action–outcome (A–O) and stimulus–response (S–R) associations underlying instrumental learning. Thus, the present study examined the long-term consequences of METH-induced neurotoxicity on A–O and S–R associations underlying appetitive instrumental behavior. Rats were pretreated with saline or a neurotoxic regimen of METH (4 × 7.5–10 mg/kg). Rats trained on random ratio (RR) or random interval (RI) schedules of reinforcement were then subjected to outcome devaluation or contingency degradation, followed by an extinction test. All rats then were killed, and brains removed for determination of striatal dopamine loss. The results show that: (1) METH pretreatment induced a partial 45–50% decrease in striatal dopamine tissue content in dorsomedial and dorsolateral striatum; (2) METH-induced neurotoxicity did not alter acquisition of instrumental behavior on either RR or RI schedules; (3) outcome devaluation and contingency degradation similarly decreased responding in saline- and METH-pretreated rats trained on the RR schedule, suggesting intact A–O associations guiding behavior; (4) outcome devaluation after training on the RI schedule decreased extinction responding only in METH-pretreated rats, suggesting impaired S–R associations. Overall, these data suggest that METH-induced neurotoxicity, possibly due to impairment of the function of dorsolateral striatal circuitry, may decrease cognitive flexibility by impairing the ability to automatize behavioral patterns. PMID:21775980

Enhancement of extinction memory consolidation: the role of the noradrenergic and GABAergic systems within the basolateral amygdala.

PubMed

Berlau, Daniel J; McGaugh, James L

2006-09-01

Evidence from previous studies indicates that the noradrenergic and GABAergic influences within the basolateral amygdala (BLA) modulate the consolidation of memory for fear conditioning. The present experiments investigated whether the same modulatory influences are involved in regulating the extinction of fear-based learning. To investigate this issue, male Sprague Dawley rats implanted with unilateral or bilateral cannula aimed at the BLA were trained on a contextual fear conditioning (CFC) task and 24 and 48 h later were given extinction training. Immediately following each extinction session they received intra-BLA infusions of the GABAergic antagonist bicuculline (50 ng), the beta-adrenocepter antagonist propranolol (500 ng), bicuculline with propranolol, norepinephrine (NE) (0.3, 1.0, and 3.0 microg), the GABAergic agonist muscimol (125 ng), NE with muscimol or a control solution. To investigate the involvement of the dorsal hippocampus (DH) as a possible target of BLA activation during extinction, other animals were given infusions of muscimol (500 ng) via an ipsilateral cannula implanted in the DH. Bilateral BLA infusions of bicuculline significantly enhanced extinction, as did infusions into the right, but not left BLA. Propranolol infused into the right BLA together with bicuculline blocked the bicuculline-induced memory enhancement. Norepinephrine infused into the right BLA also enhanced extinction, and this effect was not blocked by co-infusions of muscimol. Additionally, muscimol infused into the DH did not attenuate the memory enhancing effects of norepinephrine infused into the BLA. These findings provide evidence that, as with original CFC learning, noradrenergic activation within the BLA modulates the consolidation of CFC extinction. The findings also suggest that the BLA influence on extinction is not mediated by an interaction with the dorsal hippocampus.

Ecological response of plant consumers to Middle-Upper Pennsylvanian extinctions in Illinois Basin coal swamps: Evidence from plant/arthropod interactions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Labandeira, C.; Phillips, T.

1992-01-01

Paleobotanical studies of coal-swamp vegetation during the Middle to Upper Pennsylvanian of North America indicate major changes from lycopsid dominated to tree-fern dominated coal-swamp forests as a result of extinction. This taxonomic shift from lycopsids to tree ferns should have implications on dependent feeding guilds, such as detritivores and herbivores. Comparative coal-ball evidence from the Springfield and Herrin Coals (Carbondale Fm.) and Calhoun Coal (Mattoon Fm.) is used to address this issue. The two major feeding guilds of Pennsylvanian coal-swamps were detritivores and herbivores. Detritivores were dominant throughout the interval. Evidence suggests an increasing presence of herbivores during the Desmoinesianmore » and especially during the Missourian. Based on identifications of tissue types found in coprolite types and plant tissue damage patterns, detritivores such as oribatid mites and an unknown stem-parenchyma consumer of Psaronius tree ferns occur before and after the extinction. Based on available evidence, detritivores apparently exhibited stability, particularly since the taxonomic affiliation of their food resource shifted considerably, thus indicating dietary specificities based instead on tissue type. There is evidence for herbivory by stem-miners on Missourian age tree-fern petioles; this distinctive behavior has not been reported for Desmoinesean or older deposits. The arthropod body-fossil record is consistent with this pattern: detritivore groups such as roaches survive the extinction largely intact, whereas other groups such as diverse protorthopterans,'' some of which were most likely herbivorous, experienced a significant extinction.« less

Extinction Generates Outcome-Specific Conditioned Inhibition.

PubMed

Laurent, Vincent; Chieng, Billy; Balleine, Bernard W

2016-12-05

Extinction involves altering a previously established predictive relationship between a cue and its outcome by repeatedly presenting that cue alone. Although it is widely accepted that extinction generates some form of inhibitory learning [1-4], direct evidence for this claim has been lacking, and the nature of the associative changes induced by extinction have, therefore, remained a matter of debate [5-8]. In the current experiments, we used a novel behavioral approach that we recently developed and that provides a direct measure of conditioned inhibition [9] to compare the influence of extinguished and non-extinguished cues on choice between goal-directed actions. Using this approach, we provide direct evidence that extinction generates outcome-specific conditioned inhibition. Furthermore, we demonstrate that this inhibitory learning is controlled by the infralimbic cortex (IL); inactivation of the IL using M4 DREADDs abolished outcome-specific inhibition and rendered the cue excitatory. Importantly, we found that context modulated this inhibition. Outside its extinction context, the cue was excitatory and functioned as a specific predictor of its previously associated outcome, biasing choice toward actions earning the same outcome. In its extinction context, however, the cue acted as a specific inhibitor and biased choice toward actions earning different outcomes. Context modulation of these excitatory and inhibitory memories was mediated by the dorsal hippocampus (HPC), suggesting that the HPC and IL act in concert to control the influence of conditioned inhibitors on choice. These findings demonstrate for the first time that extinction turns a cue into a net inhibitor that can influence choice via counterfactual action-outcome associations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Impairment of contextual fear extinction by chronic nicotine and withdrawal from chronic nicotine is associated with hippocampal nAChR upregulation.

PubMed

Kutlu, Munir Gunes; Oliver, Chicora; Huang, Peng; Liu-Chen, Lee-Yuan; Gould, Thomas J

2016-10-01

Chronic nicotine and withdrawal from chronic nicotine have been shown to be major modulators of fear learning behavior. Moreover, recent studies from our laboratory have shown that acute nicotine impaired fear extinction and safety learning in mice. However, the effects of chronic nicotine and withdrawal on fear extinction are unknown. Therefore, the current experiments were conducted to investigate the effects of chronic nicotine as well as withdrawal from chronic nicotine on contextual fear extinction in mice. C57BL6/J mice were given contextual fear conditioning training and retention testing during chronic nicotine administration. Mice then received contextual fear extinction either during chronic nicotine or during withdrawal from chronic nicotine. Our results showed that contextual fear extinction was impaired both during chronic nicotine administration and subsequent withdrawal. However, it was also observed that the effects of prior chronic nicotine disappeared after 72 h in withdrawal, a timeline that closely matches with the timing of the chronic nicotine-induced upregulation of hippocampal nicotinic acetylcholine receptor (nAChR) density. Additional experiments found that 4 days, but not 1 day, of continuous nicotine administration upregulated hippocampal nAChRs and impaired contextual fear extinction. These effects disappeared following 72 h withdrawal. Overall, these experiments provide a potential link between nicotine-induced upregulation of hippocampal nAChRs and fear extinction deficits observed in patients with anxiety disorders, which may lead to advancements in the pharmacological treatment methods for this disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hunger Promotes Fear Extinction by Activation of an Amygdala Microcircuit

PubMed Central

Verma, Dilip; Wood, James; Lach, Gilliard; Herzog, Herbert; Sperk, Guenther; Tasan, Ramon

2016-01-01

Emotions control evolutionarily-conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and, in particular, the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident, their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wild-type mice and in mice with genetic modification of a feeding-related gene. Furthermore, we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, whereas fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger, suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug targets for treatment of anxiety disorders. PMID:26062787

Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning.

PubMed

Anastasio, Thomas J

2013-01-01

Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features.

Computational search for hypotheses concerning the endocannabinoid contribution to the extinction of fear conditioning

PubMed Central

Anastasio, Thomas J.

2013-01-01

Fear conditioning, in which a cue is conditioned to elicit a fear response, and extinction, in which a previously conditioned cue no longer elicits a fear response, depend on neural plasticity occurring within the amygdala. Projection neurons in the basolateral amygdala (BLA) learn to respond to the cue during fear conditioning, and they mediate fear responding by transferring cue signals to the output stage of the amygdala. Some BLA projection neurons retain their cue responses after extinction. Recent work shows that activation of the endocannabinoid system is necessary for extinction, and it leads to long-term depression (LTD) of the GABAergic synapses that inhibitory interneurons make onto BLA projection neurons. Such GABAergic LTD would enhance the responses of the BLA projection neurons that mediate fear responding, so it would seem to oppose, rather than promote, extinction. To address this paradox, a computational analysis of two well-known conceptual models of amygdaloid plasticity was undertaken. The analysis employed exhaustive state-space search conducted within a declarative programming environment. The analysis reveals that GABAergic LTD actually increases the number of synaptic strength configurations that achieve extinction while preserving the cue responses of some BLA projection neurons in both models. The results suggest that GABAergic LTD helps the amygdala retain cue memory during extinction even as the amygdala learns to suppress the previously conditioned response. The analysis also reveals which features of both models are essential for their ability to achieve extinction with some cue memory preservation, and suggests experimental tests of those features. PMID:23761759

Hunger Promotes Fear Extinction by Activation of an Amygdala Microcircuit.

PubMed

Verma, Dilip; Wood, James; Lach, Gilliard; Herzog, Herbert; Sperk, Guenther; Tasan, Ramon

2016-01-01

Emotions control evolutionarily-conserved behavior that is central to survival in a natural environment. Imbalance within emotional circuitries, however, may result in malfunction and manifestation of anxiety disorders. Thus, a better understanding of emotional processes and, in particular, the interaction of the networks involved is of considerable clinical relevance. Although neurobiological substrates of emotionally controlled circuitries are increasingly evident, their mutual influences are not. To investigate interactions between hunger and fear, we performed Pavlovian fear conditioning in fasted wild-type mice and in mice with genetic modification of a feeding-related gene. Furthermore, we analyzed in these mice the electrophysiological microcircuits underlying fear extinction. Short-term fasting before fear acquisition specifically impaired long-term fear memory, whereas fasting before fear extinction facilitated extinction learning. Furthermore, genetic deletion of the Y4 receptor reduced appetite and completely impaired fear extinction, a phenomenon that was rescued by fasting. A marked increase in feed-forward inhibition between the basolateral and central amygdala has been proposed as a synaptic correlate of fear extinction and involves activation of the medial intercalated cells. This form of plasticity was lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger, suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug targets for treatment of anxiety disorders.

Learning-related human brain activations reflecting individual finances.

PubMed

Tobler, Philippe N; Fletcher, Paul C; Bullmore, Edward T; Schultz, Wolfram

2007-04-05

A basic tenet of microeconomics suggests that the subjective value of financial gains decreases with increasing assets of individuals ("marginal utility"). Using concepts from learning theory and microeconomics, we assessed the capacity of financial rewards to elicit behavioral and neuronal changes during reward-predictive learning in participants with different financial backgrounds. Behavioral learning speed during both acquisition and extinction correlated negatively with the assets of the participants, irrespective of education and age. Correspondingly, response changes in midbrain and striatum measured with functional magnetic resonance imaging were slower during both acquisition and extinction with increasing assets and income of the participants. By contrast, asymptotic magnitudes of behavioral and neuronal responses after learning were unrelated to personal finances. The inverse relationship of behavioral and neuronal learning speed with personal finances is compatible with the general concept of decreasing marginal utility with increasing wealth.

Altered consolidation of extinction-like inhibitory learning in genotype-specific dysfunctional coping fostered by chronic stress in mice.

PubMed

Campus, P; Maiolati, M; Orsini, C; Cabib, S

2016-12-15

Genetic and stress-related factors interact to foster mental disorders, possibly through dysfunctional learning. In a previous study we reported that a temporary experience of reduced food availability increases forced swim (FS)-induced helplessness tested 14days after a first experience in mice of the standard inbred C57BL/6(B6) strain but reduces it in mice of the genetically unrelated DBA/2J (D2) strain. Because persistence of FS-induced helplessness influences adaptive coping with stress challenge and involve learning processes the present study tested whether the behavioral effects of restricted feeding involved altered consolidation of FS-related learning. First, we demonstrated that restricted feeding does not influence behavior expressed on the first FS experience, supporting a specific effect on persistence rather then development of helplessness. Second, we found that FS-induced c-fos expression in the infralimbic cortex (IL) was selectively enhanced in food-restricted (FR) B6 mice and reduced in FR D2 mice, supporting opposite alterations of consolidation processes involving this brain area. Third, we demonstrated that immediate post-FS inactivation of IL prevents 24h retention of acquired helplessness by continuously free-fed mice of both strains, indicating the requirement of a functioning IL for consolidation of FS-related learning in either mouse strain. Finally, in line with the known role of IL in consolidation of extinction memories, we found that restricted feeding selectively facilitated 24h retention of an acquired extinction in B6 mice whereas impairing it in D2 mice. These findings support the conclusion that an experience of reduced food availability strain-specifically affects persistence of newly acquired passive coping strategies by altering consolidation of extinction-like inhibitory learning. Copyright © 2016 Elsevier B.V. All rights reserved.

Infralimbic EphB2 Modulates Fear Extinction in Adolescent Rats.

PubMed

Cruz, Emmanuel; Soler-Cedeño, Omar; Negrón, Geovanny; Criado-Marrero, Marangelie; Chompré, Gladys; Porter, James T

2015-09-09

Adolescent rats are prone to impaired fear extinction, suggesting that mechanistic differences in extinction could exist in adolescent and adult rats. Since the infralimbic cortex (IL) is critical for fear extinction, we used PCR array technology to identify gene expression changes in IL induced by fear extinction in adolescent rats. Interestingly, the ephrin type B receptor 2 (EphB2), a tyrosine kinase receptor associated with synaptic development, was downregulated in IL after fear extinction. Consistent with the PCR array results, EphB2 levels of mRNA and protein were reduced in IL after fear extinction compared with fear conditioning, suggesting that EphB2 signaling in IL regulates fear extinction memory in adolescents. Finally, reducing EphB2 synthesis in IL with shRNA accelerated fear extinction learning in adolescent rats, but not in adult rats. These findings identify EphB2 in IL as a key regulator of fear extinction during adolescence, perhaps due to the increase in synaptic remodeling occurring during this developmental phase. Copyright © 2015 the authors 0270-6474/15/3512394-10$15.00/0.

Acquisition of CS-US contingencies during Pavlovian fear conditioning and extinction in social anxiety disorder and posttraumatic stress disorder.

PubMed

Rabinak, Christine A; Mori, Shoko; Lyons, Maryssa; Milad, Mohammed R; Phan, K Luan

2017-01-01

Fear-based disorders, like social anxiety disorder (SAD) and posttraumatic stress disorder (PTSD), are characterized by an exaggerated fear response and avoidance to trigger cues, suggesting a transdiagnostic mechanism of psychopathology. Current theories suggest that abnormalities in conditioned fear is a primary contributor to the pathophysiology of these disorders. The primary goal of this study was to compare acquisition of conditioned stimulus (CS) and aversive unconditioned stimulus (US) contingencies during fear learning and extinction in individuals with SAD and PTSD. In a standard Pavlovian fear conditioning-extinction paradigm we measured subjective US expectancy ratings to different CSs in patients with SAD (n=16) compared to patients with PTSD (n=13) and healthy controls (n=15) RESULTS: Both patient groups (SAD, PTSD) acquired differential conditioning between a CS that predicted US (CS+) and a CS that never predicted the US (CS-), however, both groups reported an increased expectancy that the US would occur following the CS-. Additionally, the PTSD group overestimated that the US would occur in general. Neither patient group showed evidence of successful extinction of the CS+-US contingency nor differentiated their expectation of US occurrence between the CS+ and CS- during extinction learning. Group sample sizes were small and we did not include a trauma-exposed group without PTSD CONCLUSIONS: Both SAD and PTSD generalize expectations of an aversive outcome across CSs, even when a CS never signals an aversive outcome and PTSD may tend to over-expect threat. Fear learning and extinction abnormalities may be a core feature underlying shared symptoms across fear-based disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

Negative mood reverses devaluation of goal-directed drug-seeking favouring an incentive learning account of drug dependence.

PubMed

Hogarth, Lee; He, Zhimin; Chase, Henry W; Wills, Andy J; Troisi, Joseph; Leventhal, Adam M; Mathew, Amanda R; Hitsman, Brian

2015-09-01

Two theories explain how negative mood primes smoking behaviour. The stimulus-response (S-R) account argues that in the negative mood state, smoking is experienced as more reinforcing, establishing a direct (automatic) association between the negative mood state and smoking behaviour. By contrast, the incentive learning account argues that in the negative mood state smoking is expected to be more reinforcing, which integrates with instrumental knowledge of the response required to produce that outcome. One differential prediction is that whereas the incentive learning account anticipates that negative mood induction could augment a novel tobacco-seeking response in an extinction test, the S-R account could not explain this effect because the extinction test prevents S-R learning by omitting experience of the reinforcer. To test this, overnight-deprived daily smokers (n = 44) acquired two instrumental responses for tobacco and chocolate points, respectively, before smoking to satiety. Half then received negative mood induction to raise the expected value of tobacco, opposing satiety, whilst the remainder received positive mood induction. Finally, a choice between tobacco and chocolate was measured in extinction to test whether negative mood could augment tobacco choice, opposing satiety, in the absence of direct experience of tobacco reinforcement. Negative mood induction not only abolished the devaluation of tobacco choice, but participants with a significant increase in negative mood increased their tobacco choice in extinction, despite satiety. These findings suggest that negative mood augments drug-seeking by raising the expected value of the drug through incentive learning, rather than through automatic S-R control.

Social modulation of associative fear learning by pheromone communication

PubMed Central

Bredy, Timothy W.; Barad, Mark

2009-01-01

Mice communicate through visual, vocal, and olfactory cues that influence innate, nonassociative behavior. We here report that exposure to a recently fear-conditioned familiar mouse impairs acquisition of conditioned fear and facilitates fear extinction, effects mimicked by both an olfactory chemosignal emitted by a recently fear-conditioned familiar mouse and by the putative stress-related anxiogenic pheromone β-phenylethylamine (β-PEA). Together, these findings suggest social modulation of higher-order cognitive processing through pheromone communication and support the concurrent excitor hypothesis of extinction learning. PMID:19117912

Social modulation of associative fear learning by pheromone communication.

PubMed

Bredy, Timothy W; Barad, Mark

2009-01-01

Mice communicate through visual, vocal, and olfactory cues that influence innate, nonassociative behavior. We here report that exposure to a recently fear-conditioned familiar mouse impairs acquisition of conditioned fear and facilitates fear extinction, effects mimicked by both an olfactory chemosignal emitted by a recently fear-conditioned familiar mouse and by the putative stress-related anxiogenic pheromone beta-phenylethylamine (beta-PEA). Together, these findings suggest social modulation of higher-order cognitive processing through pheromone communication and support the concurrent excitor hypothesis of extinction learning.

Social Defeat: Impact on Fear Extinction and Amygdala-Prefrontal Cortical Theta Synchrony in 5-HTT Deficient Mice

PubMed Central

Narayanan, Venu; Heiming, Rebecca S.; Jansen, Friederike; Lesting, Jörg; Sachser, Norbert; Pape, Hans-Christian; Seidenbecher, Thomas

2011-01-01

Emotions, such as fear and anxiety, can be modulated by both environmental and genetic factors. One genetic factor is for example the genetically encoded variation of the serotonin transporter (5-HTT) expression. In this context, the 5-HTT plays a key role in the regulation of central 5-HT neurotransmission, which is critically involved in the physiological regulation of emotions including fear and anxiety. However, a systematic study which examines the combined influence of environmental and genetic factors on fear-related behavior and the underlying neurophysiological basis is missing. Therefore, in this study we used the 5-HTT-deficient mouse model for studying emotional dysregulation to evaluate consequences of genotype specific disruption of 5-HTT function and repeated social defeat for fear-related behaviors and corresponding neurophysiological activities in the lateral amygdala (LA) and infralimbic region of the medial prefrontal cortex (mPFC) in male 5-HTT wild-type (+/+), homo- (−/−) and heterozygous (+/−) mice. Naive males and experienced losers (generated in a resident-intruder paradigm) of all three genotypes, unilaterally equipped with recording electrodes in LA and mPFC, underwent a Pavlovian fear conditioning. Fear memory and extinction of conditioned fear was examined while recording neuronal activity simultaneously with fear-related behavior. Compared to naive 5-HTT+/+ and +/− mice, 5-HTT−/− mice showed impaired recall of extinction. In addition, 5-HTT−/− and +/− experienced losers showed delayed extinction learning and impaired recall of extinction. Impaired behavioral responses were accompanied by increased theta synchronization between the LA and mPFC during extinction learning in 5-HTT-/− and +/− losers. Furthermore, impaired extinction recall was accompanied with increased theta synchronization in 5-HTT−/− naive and in 5-HTT−/− and +/− loser mice. In conclusion, extinction learning and memory of conditioned fear can be modulated by both the 5-HTT gene activity and social experiences in adulthood, accompanied by corresponding alterations of the theta activity in the amygdala-prefrontal cortex network. PMID:21818344

Functional gene polymorphisms in the serotonin system and traumatic life events modulate the neural basis of fear acquisition and extinction.

PubMed

Hermann, Andrea; Küpper, Yvonne; Schmitz, Anja; Walter, Bertram; Vaitl, Dieter; Hennig, Jürgen; Stark, Rudolf; Tabbert, Katharina

2012-01-01

Fear acquisition and extinction are crucial mechanisms in the etiology and maintenance of anxiety disorders. Moreover, they might play a pivotal role in conveying the influence of genetic and environmental factors on the development of a (more or less) stronger proneness for, or resilience against psychopathology. There are only few insights in the neurobiology of genetically and environmentally based individual differences in fear learning and extinction. In this functional magnetic resonance imaging study, 74 healthy subjects were investigated. These were invited according to 5-HTTLPR/rs25531 (S+ vs. L(A)L(A); triallelic classification) and TPH2 (G(-703)T) (T+ vs. T-) genotype. The aim was to investigate the influence of genetic factors and traumatic life events on skin conductance responses (SCRs) and neural responses (amygdala, insula, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC)) during acquisition and extinction learning in a differential fear conditioning paradigm. Fear acquisition was characterized by stronger late conditioned and unconditioned responses in the right insula in 5-HTTLPR S-allele carriers. During extinction traumatic life events were associated with reduced amygdala activation in S-allele carriers vs. non-carriers. Beyond that, T-allele carriers of the TPH2 (G(-703)T) polymorphism with a higher number of traumatic life events showed enhanced responsiveness in the amygdala during acquisition and in the vmPFC during extinction learning compared with non-carriers. Finally, a combined effect of the two polymorphisms with higher responses in S- and T-allele carriers was found in the dACC during extinction. The results indicate an increased expression of conditioned, but also unconditioned fear responses in the insula in 5-HTTLPR S-allele carriers. A combined effect of the two polymorphisms on dACC activation during extinction might be associated with prolonged fear expression. Gene-by-environment interactions in amygdala and vmPFC activation may reflect a neural endophenotype translating genetic and adverse environmental influences into vulnerability for or resilience against developing affective psychopathology.

Context conditioning and extinction in humans: differential contribution of the hippocampus, amygdala and prefrontal cortex

PubMed Central

Lang, Simone; Kroll, Alexander; Lipinski, Slawomira J; Wessa, Michèle; Ridder, Stephanie; Christmann, Christoph; Schad, Lothar R; Flor, Herta

2009-01-01

Functional magnetic resonance imaging was used to investigate the role of the hippocampus, amygdala and medial prefrontal cortex (mPFC) in a contextual conditioning and extinction paradigm provoking anxiety. Twenty-one healthy persons participated in a differential context conditioning procedure with two different background colours as contexts. During acquisition increased activity to the conditioned stimulus (CS+) relative to the CS− was found in the left hippocampus and anterior cingulate cortex (ACC). The amygdala, insula and inferior frontal cortex were differentially active during late acquisition. Extinction was accompanied by enhanced activation to CS+ vs. CS− in the dorsal anterior cingulate cortex (dACC). The results are in accordance with animal studies and provide evidence for the important role of the hippocampus in contextual learning in humans. Connectivity analyses revealed correlated activity between the left posterior hippocampus and dACC (BA32) during early acquisition and the dACC, left posterior hippocampus and right amygdala during extinction. These data are consistent with theoretical models that propose an inhibitory effect of the mPFC on the amygdala. The interaction of the mPFC with the hippocampus may reflect the context-specificity of extinction learning. PMID:19200075

Social anxiety modulates amygdala activation during social conditioning.

PubMed

Pejic, Tanja; Hermann, Andrea; Vaitl, Dieter; Stark, Rudolf

2013-03-01

Aversive social learning experiences might play a significant role in the aetiology of social anxiety disorder. Therefore, we investigated emotional learning and unlearning processes in healthy humans using a social conditioning paradigm. Forty-nine healthy subjects participated in a 2-day fMRI differential conditioning protocol. Acquisition and extinction were conducted on Day 1 and extinction recall on Day 2. BOLD responses, ratings and skin conductance responses were collected. Our data indicate successful conditioning and extinction on the neural and subjective level. As a main result, we observed a positive correlation of social anxiety and conditioning responses on the subjective level (valence and fear) as well as on the neural level with significant CS(+)/CS(-) differentiation in the left amygdala and the left hippocampus. Further, significant CS(+)/CS(-) differentiation in the left amygdala was found during extinction and was associated with lower scores in social anxiety. During extinction recall, we found a tendentially negative correlation of social anxiety and CS(+)/CS(-) differentiation in the vmPFC. In sum, we were able to show that social anxiety is related to conditionability with socially threatening stimuli. This could point to an important aspect in the aetiology of social anxiety disorder.

Cognitive Enhancers for Facilitating Drug Cue Extinction: Insights from Animal Models

PubMed Central

Nic Dhonnchadha, Bríd Áine; Kantak, Kathleen M.

2011-01-01

Given the success of cue exposure (extinction) therapy combined with a cognitive enhancer for reducing anxiety, it is anticipated that this approach will prove more efficacious than exposure therapy alone in preventing relapse in individuals with substance use disorders. Several factors may undermine the efficacy of exposure therapy for substance use disorders, but we suspect that neurocognitive impairments associated with chronic drug use are an important contributing factor. Numerous insights on these issues are gained from research using animal models of addiction. In this review, the relationship between brain sites whose learning, memory and executive functions are impaired by chronic drug use and brain sites that are important for effective drug cue extinction learning is explored first. This is followed by an overview of animal research showing improved treatment outcome for drug addiction (e.g. alcohol, amphetamine, cocaine, heroin) when explicit extinction training is conducted in combination with acute dosing of a cognitive-enhancing drug. The mechanism by which cognitive enhancers are thought to exert their benefits is by facilitating consolidation of drug cue extinction memory after activation of glutamatergic receptors. Based on the encouraging work in animals, factors that may be important for the treatment of drug addiction are considered. PMID:21295059

Interoceptive conditioning with the nicotine stimulus: extinction learning as a method for assessing stimulus similarity across doses.

PubMed

Polewan, Robert J; Savala, Stephanie A; Bevins, Rick A

2013-02-01

Interoceptive conditioning involving the nicotine stimulus likely contributes to chronic tobacco use. To better understand the nature of this interoceptive conditioning, we compared generalization during repeated extinction with generalization in a 'transfer of extinction' test using a wide range of test doses. Rats were first trained in the discriminated goal-tracking task in which nicotine (0.2 or 0.4 mg/kg), but not saline, was paired with repeated intermittent access to sucrose. Across sessions, nicotine acquired control of approach behavior directed at the location of previous sucrose deliveries. Extinction followed with eight 20-min sessions without sucrose access; extinction doses of nicotine ranged from 0.05 to 0.6 mg/kg. In rats trained with 0.4 mg/kg, the 0.1, 0.2, and 0.6 mg/kg doses evoked comparable responding across extinction sessions; substitution was only partial at 0.05 and 0.075 mg/kg (i.e. above saline controls, but less than the training dose). With the 0.2 mg/kg training dose, complete generalization was seen only at the 0.1 and 0.4 mg/kg doses. After extinction, rats were given a transfer test with their training dose. Rats trained with 0.4 mg/kg showed full transfer of extinction learning with 0.1, 0.2, and 0.6 mg/kg (i.e. responding comparable with extinction with the training dose). Partial transfer was observed at 0.075 mg/kg. With the 0.2 mg/kg nicotine dose, only 0.4 mg/kg fully generalized; 0.075, 0.1, and 0.6 mg/kg showed partial transfer. Extinction with 0.05 mg/kg dose did not show transfer to either training dose. These findings indicated that conclusions regarding stimulus similarity across nicotine doses can vary with testing protocol.

Cholinergic signaling controls conditioned-fear behaviors and enhances plasticity of cortical-amygdala circuits

PubMed Central

Jiang, Li; Kundu, Srikanya; Lederman, James D.; López-Hernández, Gretchen Y.; Ballinger, Elizabeth C.; Wang, Shaohua; Talmage, David A.; Role, Lorna W.

2016-01-01

Summary We examined the contribution of endogenous cholinergic signaling to the acquisition and extinction of fear- related memory by optogenetic regulation of cholinergic input to the basal lateral amygdala (BLA). Stimulation of cholinergic terminal fields within the BLA in awake-behaving mice during training in a cued fear-conditioning paradigm slowed the extinction of learned fear as assayed by multi-day retention of extinction learning. Inhibition of cholinergic activity during training reduced the acquisition of learned fear behaviors. Circuit mechanisms underlying the behavioral effects of cholinergic signaling in the BLA were assessed by in vivo and ex vivo electrophysiological recording. Photo-stimulation of endogenous cholinergic input: (1) enhances firing of putative BLA principal neurons through activation of acetylcholine receptors (AChRs); (2) enhances glutamatergic synaptic transmission in the BLA and (3) induces LTP of cortical-amygdala circuits. These studies support an essential role of cholinergic modulation of BLA circuits in the inscription and retention of fear memories. PMID:27161525

The value of vocalizing: Five-month-old infants associate their own noncry vocalizations with responses from caregivers

PubMed Central

Goldstein, Michael H.; Schwade, Jennifer A.; Bornstein, Marc H.

2014-01-01

The early noncry vocalizations of infants are salient social signals. Caregivers spontaneously respond to 30-50% of these sounds, and their responsiveness to infants' prelinguistic noncry vocalizations facilitates the development of phonology and speech. Have infants learned that their vocalizations influence the behavior of social partners? If infants have learned the contingency between their vocalizing and the social responses of others, they should show an extinction burst when the contingency is removed, increasing their rate of noncry vocalizing then decreasing. Thirty-eight 5-month-olds were tested in the still-face paradigm, during which they engaged in a 2-min still-face interaction with an unfamiliar adult. When the adult assumed a still face, infants showed an extinction burst. This pattern of infant vocalizations suggests that 5-month-olds have learned the social efficacy of their vocalizations on caregivers' behavior. Furthermore, the magnitude of 5-month infants' extinction bursts predicted their language comprehension at 13 months. PMID:19489893

A System Computational Model of Implicit Emotional Learning

PubMed Central

Puviani, Luca; Rama, Sidita

2016-01-01

Nowadays, the experimental study of emotional learning is commonly based on classical conditioning paradigms and models, which have been thoroughly investigated in the last century. Unluckily, models based on classical conditioning are unable to explain or predict important psychophysiological phenomena, such as the failure of the extinction of emotional responses in certain circumstances (for instance, those observed in evaluative conditioning, in post-traumatic stress disorders and in panic attacks). In this manuscript, starting from the experimental results available from the literature, a computational model of implicit emotional learning based both on prediction errors computation and on statistical inference is developed. The model quantitatively predicts (a) the occurrence of evaluative conditioning, (b) the dynamics and the resistance-to-extinction of the traumatic emotional responses, (c) the mathematical relation between classical conditioning and unconditioned stimulus revaluation. Moreover, we discuss how the derived computational model can lead to the development of new animal models for resistant-to-extinction emotional reactions and novel methodologies of emotions modulation. PMID:27378898

A System Computational Model of Implicit Emotional Learning.

PubMed

Puviani, Luca; Rama, Sidita

2016-01-01

Nowadays, the experimental study of emotional learning is commonly based on classical conditioning paradigms and models, which have been thoroughly investigated in the last century. Unluckily, models based on classical conditioning are unable to explain or predict important psychophysiological phenomena, such as the failure of the extinction of emotional responses in certain circumstances (for instance, those observed in evaluative conditioning, in post-traumatic stress disorders and in panic attacks). In this manuscript, starting from the experimental results available from the literature, a computational model of implicit emotional learning based both on prediction errors computation and on statistical inference is developed. The model quantitatively predicts (a) the occurrence of evaluative conditioning, (b) the dynamics and the resistance-to-extinction of the traumatic emotional responses, (c) the mathematical relation between classical conditioning and unconditioned stimulus revaluation. Moreover, we discuss how the derived computational model can lead to the development of new animal models for resistant-to-extinction emotional reactions and novel methodologies of emotions modulation.

Involvement of the basolateral amygdala in muscarinic cholinergic modulation of extinction memory consolidation

PubMed Central

Boccia, Mariano M.; Blake, Mariano G.; Baratti, Carlos M.; McGaugh, James L.

2009-01-01

Previous studies have reported that drugs affecting neuromodulatory systems within the basolateral amygdala (BLA), including drugs affecting muscarinic cholinergic receptors, modulate the consolidation of many kinds of training, including contextual fear conditioning (CFC). The present experiments investigated the involvement of muscarinic cholinergic influences within the BLA in modulating the consolidation of CFC extinction memory. Male Sprague Dawley rats implanted with unilateral cannula aimed at the BLA were trained on a CFC task, using footshock stimulation, and 24 and 48 h later were given extinction training by replacing them in the apparatus without footshock. Following each extinction session they received intra-BLA infusions of the cholinergic agonist oxotremorine (10 ng). Immediate post-extinction BLA infusions significantly enhanced extinction but infusions administered 180 min after extinction training did not influence extinction. Thus the oxotremorine effects were time-dependent and not attributable to non-specific effects on retention performance. These findings provide evidence that, as previously found with original CFC learning, cholinergic activation within the BLA modulates the consolidation of CFC extinction. PMID:18706510

Tropical forests and the changing earth system.

PubMed

Lewis, Simon L

2006-01-29

Tropical forests are global epicentres of biodiversity and important modulators of the rate of climate change. Recent research on deforestation rates and ecological changes within intact forests, both areas of recent research and debate, are reviewed, and the implications for biodiversity (species loss) and climate change (via the global carbon cycle) addressed. Recent impacts have most likely been: (i) a large source of carbon to the atmosphere, and major loss of species, from deforestation and (ii) a large carbon sink within remaining intact forest, accompanied by accelerating forest dynamism and widespread biodiversity changes. Finally, I look to the future, suggesting that the current carbon sink in intact forests is unlikely to continue, and that the tropical forest biome may even become a large net source of carbon, via one or more of four plausible routes: changing photosynthesis and respiration rates, biodiversity changes in intact forest, widespread forest collapse via drought, and widespread forest collapse via fire. Each of these scenarios risks potentially dangerous positive feedbacks with the climate system that could dramatically accelerate and intensify climate change. Given that continued land-use change alone is already thought to be causing the sixth mass extinction event in Earth's history, should such feedbacks occur, the resulting biodiversity and societal consequences would be even more severe.

HDAC3-selective inhibitor enhances extinction of cocaine-seeking behavior in a persistent manner.

PubMed

Malvaez, Melissa; McQuown, Susan C; Rogge, George A; Astarabadi, Mariam; Jacques, Vincent; Carreiro, Samantha; Rusche, James R; Wood, Marcelo A

2013-02-12

Nonspecific histone deacetylase (HDAC) inhibition has been shown to facilitate the extinction of drug-seeking behavior in a manner resistant to reinstatement. A key open question is which specific HDAC is involved in the extinction of drug-seeking behavior. Using the selective HDAC3 inhibitor RGFP966, we investigated the role of HDAC3 in extinction and found that systemic treatment with RGFP966 facilitates extinction in mice in a manner resistant to reinstatement. We also investigated whether the facilitated extinction is related to the enhancement of extinction consolidation during extinction learning or to negative effects on performance or reconsolidation. These are key distinctions with regard to any compound being used to modulate extinction, because a more rapid decrease in a defined behavior is interpreted as facilitated extinction. Using an innovative combination of behavioral paradigms, we found that a single treatment of RGFP966 enhances extinction of a previously established cocaine-conditioned place preference, while simultaneously enhancing long-term object-location memory within subjects. During extinction consolidation, HDAC3 inhibition promotes a distinct pattern of histone acetylation linked to gene expression within the infralimbic cortex, hippocampus, and nucleus accumbens. Thus, the facilitated extinction of drug-seeking cannot be explained by adverse effects on performance. These results demonstrate that HDAC3 inhibition enhances the memory processes involved in extinction of drug-seeking behavior.

A unifying model of the role of the infralimbic cortex in extinction and habits

PubMed Central

Taylor, Jane R.; Chandler, L. Judson

2014-01-01

The infralimbic prefrontal cortex (IL) has been shown to be critical for the regulation of flexible behavior, but its precise function remains unclear. This region has been shown to be critical for the acquisition, consolidation, and expression of extinction learning, leading many to hypothesize that IL suppresses behavior as part of a “stop” network. However, this framework is at odds with IL function in habitual behavior in which the IL has been shown to be required for the expression and acquisition of ongoing habitual behavior. Here, we will review the current state of knowledge of IL anatomy and function in behavioral flexibility and provide a testable framework for a single IL mechanism underlying its function in both extinction and habit learning. PMID:25128534

Rescaling of temporal expectations during extinction

PubMed Central

Drew, Michael R.; Walsh, Carolyn; Balsam, Peter D

2016-01-01

Previous research suggests that extinction learning is temporally specific. Changing the CS duration between training and extinction can facilitate the loss of the CR within the extinction session but impairs long-term retention of extinction. In two experiments using conditioned magazine approach with rats, we examined the relation between temporal specificity of extinction and CR timing. In Experiment 1 rats were trained on a 12-s, fixed CS-US interval and then extinguished with CS presentations that were 6, 12, or 24 s in duration. The design of Experiment 2 was the same except rats were trained using partial rather than continuous reinforcement. In both experiments, extending the CS duration in extinction facilitated the diminution of CRs during the extinction session, but shortening the CS duration failed to slow extinction. In addition, extending (but not shortening) the CS duration caused temporal rescaling of the CR, in that the peak CR rate migrated later into the trial over the course of extinction training. This migration partially accounted for the faster loss of the CR when the CS duration was extended. Results are incompatible with the hypothesis that extinction is driven by cumulative CS exposure and suggest that temporally extended nonreinforced CS exposure reduces conditioned responding via temporal displacement rather than through extinction per se. PMID:28045291

Updating appetitive memory during reconsolidation window: critical role of cue-directed behavior and amygdala central nucleus.

PubMed

Olshavsky, Megan E; Song, Bryan J; Powell, Daniel J; Jones, Carolyn E; Monfils, Marie-H; Lee, Hongjoo J

2013-01-01

When presented with a light cue followed by food, some rats simply approach the foodcup (Nonorienters), while others first orient to the light in addition to displaying the food-cup approach behavior (Orienters). Cue-directed orienting may reflect enhanced attentional and/or emotional processing of the cue, suggesting divergent natures of cue-information processing in Orienters and Nonorienters. The current studies investigate how differences in cue processing might manifest in appetitive memory retrieval and updating using a paradigm developed to persistently attenuate fear responses (Retrieval-extinction paradigm; Monfils et al., 2009). First, we examined whether the retrieval-extinction paradigm could attenuate appetitive responses in Orienters and Nonorienters. Next, we investigated if the appetitive memory could be updated using reversal learning (fear conditioning) during the reconsolidation window (as opposed to repeated unreinforced trials, i.e., extinction). Both extinction and new fear learning given within the reconsolidation window were effective at persistently updating the initial appetitive memory in the Orienters, but not the Nonorienters. Since conditioned orienting is mediated by the amygdala central nucleus (CeA), our final experiment examined the CeA's role in the retrieval-extinction process. Bilateral CeA lesions interfered with the retrieval-extinction paradigm-did not prevent spontaneous recovery of food-cup approach. Together, our studies demonstrate the critical role of conditioned orienting behavior and the CeA in updating appetitive memory during the reconsolidation window.

Effect of low doses of delta9-tetrahydrocannabinol and cannabidiol on the extinction of cocaine-induced and amphetamine-induced conditioned place preference learning in rats.

PubMed

Parker, Linda A; Burton, Page; Sorge, Robert E; Yakiwchuk, Christine; Mechoulam, Raphael

2004-09-01

Using the place-preference conditioning paradigm, we evaluated the potential of the two most prominent cannabinoids found in marijuana, the psychoactive component delta9-tetrahydrocannabinol (delta9-THC) and the nonpsychoactive component cannabidiol (CBD), to potentiate extinction of a cocaine-induced and an amphetamine-induced conditioned place preference in rats. To determine the effects of pretreatment with delta9-THC or CBD on extinction, a cocaine-induced and amphetamine-induced place preference was first established. Rats were then given an extinction trial, during which they were confined to the treatment-paired floor for 15 min. Thirty minutes prior to the extinction trial, they were injected with a low dose of delta9-THC (0.5 mg/kg), CBD (5 mg/kg) or vehicle. The potential of the CB1 receptor antagonist, SR141716, to reverse the effects of delta9-THC or CBD was also evaluated. To determine the hedonic effects of CBD, one distinctive floor was paired with CBD (5 mg/kg) and another with saline. Finally, to determine the effect of delta9-THC.or CBD on the establishment and/or the expression of a place preference during four cycles of conditioning trials, rats were injected with delta9-THC (0.25-1 mg/kg), CBD (5 mg/kg) or vehicle 25 min prior to receiving an injection of amphetamine followed by placement on the treatment floor; on alternate days, they received injections of vehicle followed by saline and placement on the nontreatment floor. The rats then received two test trials; on one trial they were pretreated with the cannabinoid and on the other trial with vehicle. delta9-THC and CBD potentiated the extinction of both cocaine-induced and amphetamine-induced conditioned place preference learning, and this effect was not reversed by SR141716. The cannabinoids did not affect learning or retrieval, and CBD was not hedonic on its own. These results are the first to show that both delta9-THC, which acts on both CB 1 and CB2 receptors, and CBD, which does not bind to CB1 or CB2 receptors, potentiate the extinction of conditioned incentive learning.

Suppression of Striatal Prediction Errors by the Prefrontal Cortex in Placebo Hypoalgesia.

PubMed

Schenk, Lieven A; Sprenger, Christian; Onat, Selim; Colloca, Luana; Büchel, Christian

2017-10-04

Classical learning theories predict extinction after the discontinuation of reinforcement through prediction errors. However, placebo hypoalgesia, although mediated by associative learning, has been shown to be resistant to extinction. We tested the hypothesis that this is mediated by the suppression of prediction error processing through the prefrontal cortex (PFC). We compared pain modulation through treatment cues (placebo hypoalgesia, treatment context) with pain modulation through stimulus intensity cues (stimulus context) during functional magnetic resonance imaging in 48 male and female healthy volunteers. During acquisition, our data show that expectations are correctly learned and that this is associated with prediction error signals in the ventral striatum (VS) in both contexts. However, in the nonreinforced test phase, pain modulation and expectations of pain relief persisted to a larger degree in the treatment context, indicating that the expectations were not correctly updated in the treatment context. Consistently, we observed significantly stronger neural prediction error signals in the VS in the stimulus context compared with the treatment context. A connectivity analysis revealed negative coupling between the anterior PFC and the VS in the treatment context, suggesting that the PFC can suppress the expression of prediction errors in the VS. Consistent with this, a participant's conceptual views and beliefs about treatments influenced the pain modulation only in the treatment context. Our results indicate that in placebo hypoalgesia contextual treatment information engages prefrontal conceptual processes, which can suppress prediction error processing in the VS and lead to reduced updating of treatment expectancies, resulting in less extinction of placebo hypoalgesia. SIGNIFICANCE STATEMENT In aversive and appetitive reinforcement learning, learned effects show extinction when reinforcement is discontinued. This is thought to be mediated by prediction errors (i.e., the difference between expectations and outcome). Although reinforcement learning has been central in explaining placebo hypoalgesia, placebo hypoalgesic effects show little extinction and persist after the discontinuation of reinforcement. Our results support the idea that conceptual treatment beliefs bias the neural processing of expectations in a treatment context compared with a more stimulus-driven processing of expectations with stimulus intensity cues. We provide evidence that this is associated with the suppression of prediction error processing in the ventral striatum by the prefrontal cortex. This provides a neural basis for persisting effects in reinforcement learning and placebo hypoalgesia. Copyright © 2017 the authors 0270-6474/17/379715-09$15.00/0.

The Type 3 Adenylyl Cyclase is Required for Novel Object Learning and Extinction of Contextual Memory: Role of cAMP Signaling in Primary Cilia

PubMed Central

Wang, Zhenshan; Phan, Trongha; Storm, Daniel R.

2011-01-01

Although primary cilia are found on neurons throughout the brain, their physiological function remains elusive. Human ciliopathies are associated with cognition defects and transgenic mice lacking proteins expressed in primary cilia exhibit defects in learning and memory. Recently, it was reported that mice lacking the G-protein coupling receptor somatostatin receptor-3 (SSTR3), a protein expressed predominately in the primary cilia of neurons, have defective memory for novel object recognition and lower cAMP levels in the brain. Since SSTR3 is coupled to regulation of adenylyl cyclase this suggests that adenylyl cyclase activity in primary cilia of CNS neurons may be critical for some forms of learning and memory. Because the type 3 adenylyl cyclase (AC3) is expressed in primary cilia of hippocampal neurons, we examined AC3−/− mice for several forms of learning and memory. Here, we report that AC3−/− mice show no short-term memory for novel objects and fail to exhibit extinction of contextual fear conditioning. They also show impaired learning and memory for temporally dissociated passive avoidance (TDPA). Since AC3 is exclusively expressed in primary cilia we conclude that cAMP signals generated within primary cilia contribute to some forms of learning and memory including extinction of contextual fear conditioning. PMID:21490195

The type 3 adenylyl cyclase is required for novel object learning and extinction of contextual memory: role of cAMP signaling in primary cilia.

PubMed

Wang, Zhenshan; Phan, Trongha; Storm, Daniel R

2011-04-13

Although primary cilia are found on neurons throughout the brain, their physiological function remains elusive. Human ciliopathies are associated with cognition defects, and transgenic mice lacking proteins expressed in primary cilia exhibit defects in learning and memory. Recently, it was reported that mice lacking the G-protein-coupling receptor somatostatin receptor-3 (SSTR3), a protein expressed predominately in the primary cilia of neurons, have defective memory for novel object recognition and lower cAMP levels in the brain. Since SSTR3 is coupled to regulation of adenylyl cyclase, this suggests that adenylyl cyclase activity in primary cilia of CNS neurons may be critical for some forms of learning and memory. Because the type 3 adenylyl cyclase (AC3) is expressed in primary cilia of hippocampal neurons, we examined AC3(-/-) mice for several forms of learning and memory. Here, we report that AC3(-/-) mice show no short-term memory for novel objects and fail to exhibit extinction of contextual fear conditioning. They also show impaired learning and memory for temporally dissociative passive avoidance. Since AC3 is exclusively expressed in primary cilia, we conclude that cAMP signals generated within primary cilia contribute to some forms of learning and memory, including extinction of contextual fear conditioning.

Reinstatement in Honeybees Is Context-Dependent

ERIC Educational Resources Information Center

Plath, Jenny Aino; Felsenberg, Johannes; Eisenhardt, Dorothea

2012-01-01

During extinction animals experience that the previously learned association between a conditioned stimulus (CS) and an unconditioned stimulus (US) no longer holds true. Accordingly, the conditioned response (CR) to the CS decreases. This decrease of the CR can be reversed by presentation of the US alone following extinction, a phenomenon termed…

Extinction Circuits for Fear and Addiction Overlap in Prefrontal Cortex

ERIC Educational Resources Information Center

Peters, Jamie; Kalivas, Peter W.; Quirk, Gregory J.

2009-01-01

Extinction is a form of inhibitory learning that suppresses a previously conditioned response. Both fear and drug seeking are conditioned responses that can lead to maladaptive behavior when expressed inappropriately, manifesting as anxiety disorders and addiction, respectively. Recent evidence indicates that the medial prefrontal cortex (mPFC) is…

Implicit perceptual-motor skill learning in mild cognitive impairment and Parkinson's disease.

PubMed

Gobel, Eric W; Blomeke, Kelsey; Zadikoff, Cindy; Simuni, Tanya; Weintraub, Sandra; Reber, Paul J

2013-05-01

Implicit skill learning is hypothesized to depend on nondeclarative memory that operates independent of the medial temporal lobe (MTL) memory system and instead depends on cortico striatal circuits between the basal ganglia and cortical areas supporting motor function and planning. Research with the Serial Reaction Time (SRT) task suggests that patients with memory disorders due to MTL damage exhibit normal implicit sequence learning. However, reports of intact learning rely on observations of no group differences, leading to speculation as to whether implicit sequence learning is fully intact in these patients. Patients with Parkinson's disease (PD) often exhibit impaired sequence learning, but this impairment is not universally observed. Implicit perceptual-motor sequence learning was examined using the Serial Interception Sequence Learning (SISL) task in patients with amnestic Mild Cognitive Impairment (MCI; n = 11) and patients with PD (n = 15). Sequence learning in SISL is resistant to explicit learning and individually adapted task difficulty controls for baseline performance differences. Patients with MCI exhibited robust sequence learning, equivalent to healthy older adults (n = 20), supporting the hypothesis that the MTL does not contribute to learning in this task. In contrast, the majority of patients with PD exhibited no sequence-specific learning in spite of matched overall task performance. Two patients with PD exhibited performance indicative of an explicit compensatory strategy suggesting that impaired implicit learning may lead to greater reliance on explicit memory in some individuals. The differences in learning between patient groups provides strong evidence in favor of implicit sequence learning depending solely on intact basal ganglia function with no contribution from the MTL memory system.

Integration of contextual cues into memory depends on "prefrontal" N-methyl-D-aspartate receptors.

PubMed

Starosta, Sarah; Bartetzko, Isabelle; Stüttgen, Maik C; Güntürkün, Onur

2017-10-01

Every learning event is embedded in a context, but not always does the context become an integral part of the memory; however, for extinction learning it usually does, resulting in context-specific conditioned responding. The neuronal mechanisms underlying contextual control have been mainly investigated for Pavlovian fear extinction with a focus on hippocampal structures. However, the initial acquisition of novel responses can be subject to contextual control as well, although the neuronal mechanisms are mostly unknown. Here, we tested the hypothesis that contextual control of acquisition depends on glutamatergic transmission underlying executive functions in forebrain areas, e.g. by shifting attention to critical cues. Thus, we antagonized N-methyl-D-aspartate (NMDA) receptors with 2-amino-5-phosphonovaleric acid (AP5) in the pigeon nidopallium caudolaterale, the functional analogue of mammalian prefrontal cortex, during the concomitant acquisition and extinction of conditioned responding to two different stimuli. This paradigm has previously been shown to lead to contextual control over extinguished as well as non-extinguished responding. NMDA receptor blockade resulted in an impairment of extinction learning, but left the acquisition of responses to a novel stimulus unaffected. Critically, when responses were tested in a different context in the retrieval phase, we observed that NMDA receptor blockade led to the abolishment of contextual control over acquisition performance. This result is predicted by a model describing response inclination as the product of associative strength and contextual gain. In this model, learning under AP5 leads to a change in the contextual gain on the learned association, possibly via the modulation of attentional mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of 7,8-Dihydroxyflavone, a Small-Molecule TrkB Agonist, on Emotional Learning

PubMed Central

Andero, Raul; Heldt, Scott A.; Ye, Keqiang; Liu, Xia; Armario, Antonio; Ressler, Kerry J.

2013-01-01

Objective Despite increasing awareness of the many important roles played by brain-derived neurotrophic factor (BDNF) activation of TrkB, a fuller understanding of this system and the use of potential TrkB-acting therapeutic agents has been limited by the lack of any identified small-molecule TrkB agonists that fully mimic the actions of BDNF at brain TrkB receptors in vivo. However, 7,8-dihydroxyflavone (7,8-DHF) has recently been identified as a specific TrkB agonist that crosses the blood-brain barrier after oral or intra-peritoneal administration. The authors combined pharmacological, biochemical, and behavioral approaches in a preclinical study examining the role of 7,8-DHF in modulating emotional memory in mice. Method The authors first examined the ability of systemic 7,8-DHF to activate TrkB receptors in the amygdala. They then examined the effects of systemic 7,8-DHF on acquisition and extinction of conditioned fear, using specific and well-characterized BDNF-dependent learning paradigms in several models using naive mice and mice with prior traumatic stress exposure. Results Amygdala TrkB receptors, which have previously been shown to be required for emotional learning, were activated by systemic 7,8-DHF (at 5 mg/kg i.p.). 7,8-DHF enhanced both the acquisition of fear and its extinction. It also appeared to rescue an extinction deficit in mice with a history of immobilization stress. Conclusions These data suggest that 7,8-DHF may be an excellent agent for use in understanding the effects of TrkB activation in learning and memory paradigms and may be attractive for use in reversing learning and extinction deficits associated with psychopathology. PMID:21123312

Early-life inflammation with LPS delays fear extinction in adult rodents.

PubMed

Doenni, V M; Song, C M; Hill, M N; Pittman, Q J

2017-07-01

A large body of evidence has been brought forward connecting developmental immune activation to abnormal fear and anxiety levels. Anxiety disorders have extremely high lifetime prevalence, yet susceptibility factors that contribute to their emergence are poorly understood. In this research we investigated whether an inflammatory insult early in life can alter the response to fear conditioning in adulthood. Fear learning and extinction are important and adaptive behaviors, mediated largely by the amygdala and its interconnectivity with cortico-limbic circuits. Male and female rat pups were given LPS (100μg/kg i.p.) or saline at postnatal day 14; LPS activated cFos expression in the central amygdala 2.5h after exposure, but not the basal or lateral nuclei. When tested in adulthood, acquisition of an auditory cued or contextual learned fear memory was largely unaffected as was the extinction of fear to a conditioned context. However, we detected a deficit in auditory fear extinction in male and female rats that experienced early-life inflammation, such that there is a significant delay in fear extinction processes resulting in more sustained fear behaviors in response to a conditioned cue. This response was specific to extinction training and did not persist into extinction recall. The effect could not be explained by differences in pain threshold (unaltered) or in baseline anxiety, which was elevated in adolescent females only and unaltered in adolescent males and adult males and females. This research provides further evidence for the involvement of the immune system during development in the shaping of fear and anxiety related behaviors. Copyright © 2016 Elsevier Inc. All rights reserved.

Endogenous cortisol reactivity moderates the relationship between fear inhibition to safety signals and posttraumatic stress disorder symptoms.

PubMed

Zuj, Daniel V; Palmer, Matthew A; Malhi, Gin S; Bryant, Richard A; Felmingham, Kim L

2017-04-01

Posttraumatic stress symptoms (PTSS) are commonly associated with impairments in extinguishing fear to signals previously associated with danger, and also with inhibiting fear to safety signals. Previous studies indicate that PTSS are associated with low cortisol activity, and cortisol is shown to facilitate fear extinction. Few studies have examined the influence of cortisol reactivity on fear extinction in PTSS. We used a standardized fear conditioning and extinction paradigm to investigate the relationship between fear extinction and endogenous salivary cortisol activity in participants with high PTSS (n=18), trauma-exposed controls (n=33), and non-trauma-exposed controls (n=27). Skin conductance response (SCR) was used as an index of conditioned responding. Saliva samples were collected at baseline, and 20min post-fear acquisition for basal and reactive cortisol levels, respectively. PTSS participants demonstrated a slower rate of extinction learning during the early extinction phase. A moderation analysis revealed that cortisol reactivity was a significant moderator between fear inhibition to the safety signal (CS-) during early extinction and PTSS, but not to the threat signal (CS+). Specifically, this interaction was significant in two ways: (1) participants with elevated cortisol reactivity showed lower PTSS as fear inhibition improved; and (2) participants with low cortisol reactivity showed higher PTSS as fear inhibition improved. The findings of the present study show that the relationship between fear inhibition and cortisol reactivity is complex, and suggest that cortisol reactivity shapes safety signal learning in PTSS. Copyright © 2017 Elsevier Ltd. All rights reserved.

NPY controls fear conditioning and fear extinction by combined action on Y₁ and Y₂ receptors.

PubMed

Verma, D; Tasan, R O; Herzog, H; Sperk, G

2012-06-01

Neuropeptide Y (NPY) and its receptors have been implicated in the control of emotional-affective processing, but the mechanism is unclear. While it is increasingly evident that stimulation of Y₁ and inhibition of Y₂ receptors produce prominent anxiolytic and antidepressant effects, the contribution of the individual NPY receptor subtypes in the acquisition and extinction of learned fear are unknown. Here we performed Pavlovian fear conditioning and extinction in NPY knockout (KO) and in NPY receptor KO mice. NPY KO mice display a dramatically accelerated acquisition of conditioned fear. Deletion of Y₁ receptors revealed only a moderately accelerated acquisition of conditioned fear, while lack of Y₂ receptors was without any effect on fear learning. However, the strong phenotype seen in NPY KO mice was reproduced in mice lacking both Y₁ and Y₂ receptors. In addition, NPY KO mice showed excessive recall of conditioned fear and impaired fear extinction. This behaviour was replicated only after deletion of both Y₁ and Y₂ receptors. In Y₁ receptor single KO mice, fear extinction was delayed and was unchanged in Y₂ receptor KO mice. Deletion of NPY and particularly Y₂ receptors resulted in a generalization of conditioned fear. Our data demonstrate that NPY delays the acquisition, reduces the expression of conditioned fear while promoting fear extinction. Although these effects appear to be primarily mediated by Y₁ receptors, the pronounced phenotype of Y₁Y₂ receptor double KO mice suggests a synergistic role of Y₂ receptors in fear acquisition and in fear extinction. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Narrowing down the conditions for extinction of Pavlovian feature-positive discriminations in humans.

PubMed

van Vooren, Priya R; Franssen, Mathijs; Beckers, Tom; Hermans, Dirk; Baeyens, Frank

2012-12-01

The aim of this study was to delineate the minimal conditions for extinction of Pavlovian modulation in humans. Previous experiments at our lab showed that, after X-- A+/A- acquisition training, X- trials did not extinguish differential X-- A+/A- responding, while X-- A- trials did. Additionally, X-- A- extinction training seemed only to extinguish differential X-- A+/A- responding, while leaving differential responding on a concurrently trained Y [Symbol: see text] B+/B- discrimination intact. It thus seemed that the X-- A+/A- discrimination can only be extinguished by X-- A- extinction trials. (Rescorla, Journal of Experimental Psychology: Animal Behavior Processes 12, 16-24, 1986), on the other hand, found that the minimal conditions for extinction were broader in pigeons: Namely, he found that an acquired X-- A+/A- discrimination could be extinguished by presenting the original feature X in combination with a different target (B) that was minimally trained as an exciter. We thus wanted to examine whether this was also the case in humans. We found that nonreinforced X-- B- presentations did not abolish discriminative X-- A/A responding when target B was a nonreinforced stimulus. Nonreinforced X-- B- trials did extinguish the X-- A+/A- discrimination when target B had previously been trained as a target for modulation (X-- B+/B- or Y [Symbol: see text] B+/B- training) or as a reinforced exciter (B+). Our results thusf parallel and extend those in nonhuman animals (Rescorla, Journal of Experimental Psychology: Animal Behavior Processes 12, 16-24, 1986).

Fear conditioning and extinction across development: Evidence from human studies and animal models☆

PubMed Central

Shechner, Tomer; Hong, Melanie; Britton, Jennifer C.; Pine, Daniel S.; Fox, Nathan A.

2015-01-01

The ability to differentiate danger and safety through associative processes emerges early in life. Understanding the mechanisms underlying associative learning of threat and safety can clarify the processes that shape development of normative fears and pathological anxiety. Considerable research has used fear conditioning and extinction paradigms to delineate underlying mechanisms in animals and human adults; however, little is known about these mechanisms in children and adolescents. The current paper summarizes the empirical data on the development of fear conditioning and extinction. It reviews methodological considerations and future directions for research on fear conditioning and extinction in pediatric populations. PMID:24746848

Duration of extinction trials as a determinant of instrumental extinction in terrestrial toads (Rhinella arenarum).

PubMed

Puddington, Martín M; Papini, Mauricio R; Muzio, Rubén N

2018-01-01

Instrumental learning guides behavior toward resources. When such resources are no longer available, approach to previously reinforced locations is reduced, a process called extinction. The present experiments are concerned with factors affecting the extinction of acquired behaviors in toads. In previous experiments, total reward magnitude in acquisition and duration of extinction trials were confounded. The present experiments were designed to test the effects of these factors in factorial designs. Experiment 1 varied reward magnitude (900, 300, or 100 s of water access per trial) and amount of acquisition training (5 or 15 daily trials). With total amount of water access equated in acquisition, extinction with large rewards was faster (longer latencies in 900/5 than 300/15), but with total amount of training equated, extinction with small rewards was faster (longer latencies in 100/15 than 300/15). Experiment 2 varied reward magnitude (1200 or 120 s of water access per trial) while holding constant the number of acquisition trials (5 daily trials) and the duration of extinction trials (300 s). Extinction performance was lower with small, rather than large reward magnitude (longer latencies in 120/300 than in 1200/300). Thus, instrumental extinction depends upon the amount of time toads are exposed to the empty goal compartment during extinction trials.

Cortisol modifies extinction learning of recently acquired fear in men

PubMed Central

Hermann, Andrea; Stark, Rudolf; Wolf, Oliver Tobias

2014-01-01

Exposure therapy builds on the mechanism of fear extinction leading to decreased fear responses. How the stress hormone cortisol affects brain regions involved in fear extinction in humans is unknown. For this reason, we tested 32 men randomly assigned to receive either 30 mg hydrocortisone or placebo 45 min before fear extinction. In fear acquisition, a picture of a geometrical figure was either partially paired (conditioned stimulus; CS+) or not paired (CS−) with an electrical stimulation (unconditioned stimulus; UCS). In fear extinction, each CS was presented again, but no UCS occurred. Cortisol increased conditioned skin conductance responses in early and late extinction. In early extinction, higher activation towards the CS− than to the CS+ was found in the amygdala, hippocampus and posterior parahippocampal gyrus. This pattern might be associated with the establishment of a new memory trace. In late extinction, the placebo compared with the cortisol group displayed enhanced CS+/CS− differentiation in the amygdala, medial frontal cortex and nucleus accumbens. A change from early deactivation to late activation of the extinction circuit as seen in the placebo group seems to be needed to enhance extinction and to reduce fear. Cortisol appears to interfere with this process thereby impairing extinction of recently acquired conditioned fear. PMID:23945999

Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress

PubMed Central

Fitzgerald, Paul J.; Giustino, Thomas F.; Seemann, Jocelyn R.; Maren, Stephen

2015-01-01

Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a β-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that β-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma. PMID:26124100

Extinction of drug- and withdrawal-paired cues in animal models: relevance to the treatment of addiction.

PubMed

Myers, Karyn M; Carlezon, William A

2010-11-01

Conditioned drug craving and withdrawal elicited by cues paired with drug use or acute withdrawal are among the many factors contributing to compulsive drug taking. Understanding how to stop these cues from having these effects is a major goal of addiction research. Extinction is a form of learning in which associations between cues and the events they predict are weakened by exposure to the cues in the absence of those events. Evidence from animal models suggests that conditioned responses to drug cues can be extinguished, although the degree to which this occurs in humans is controversial. Investigations into the neurobiological substrates of extinction of conditioned drug craving and withdrawal may facilitate the successful use of drug cue extinction within clinical contexts. While this work is still in the early stages, there are indications that extinction of drug- and withdrawal-paired cues shares neural mechanisms with extinction of conditioned fear. Using the fear extinction literature as a template, it is possible to organize the observations on drug cue extinction into a cohesive framework. Copyright © 2010 Elsevier Ltd. All rights reserved.

Neuronal activity-regulated pentraxin expressed in medial prefrontal cortex neurons is not necessary for extinction of heroin self-administration.

PubMed

Blouin, Ashley M; Stern, Anna L; Han, Sungho; Theberge, Florence R; Wang, Chuansong; During, Matthew J; Baraban, Jay M; Reti, Irving M

2013-08-01

The medial prefrontal cortex (mPFC) plays a key role in extinction learning. Previously, we found that expression of a neuronal activity-regulated pentraxin (Narp) dominant-negative construct in the mPFC of mice blocked extinction of morphine-conditioned place preference. To further investigate the role of mPFC Narp in the extinction of drug seeking, we tested whether mPFC Narp is necessary for the extinction of heroin self-administration in rats. Specifically, we injected an adeno-associated viral vector expressing a dominant-negative form of Narp (NarpN) into the infralimbic region of the mPFC of rats and compared lever presses during extinction to those of rats injected with a control virus. In contrast to our previous study, we found that injection of NarpN did not affect extinction of heroin self-administration. Our findings suggest that mPFC Narp is necessary for extinction of opiate seeking in the Pavlovian-conditioned place preference paradigm but not in the operant paradigm of drug self-administration.

New approaches to addiction treatment based on learning and memory.

PubMed

Kiefer, Falk; Dinter, Christina

2013-01-01

Preclinical studies suggest that physiological learning processes are similar to changes observed in addicts at the molecular, neuronal, and structural levels. Based on the importance of classical and instrumental conditioning in the development and maintenance of addictive disorders, many have suggested cue-exposure-based extinction training of conditioned, drug-related responses as a potential new treatment of addiction. It may also be possible to facilitate this extinction training with pharmacological compounds that strengthen memory consolidation during cue exposure. Another potential therapeutic intervention would be based on the so-called reconsolidation theory. According to this hypothesis, already-consolidated memories return to a labile state when reactivated, allowing them to undergo another phase of consolidation-reconsolidation, which can be pharmacologically manipulated. These approaches suggest that the extinction of drug-related memories may represent a viable treatment strategy in the future treatment of addiction.

Acute exercise enhances the consolidation of fear extinction memory and reduces conditioned fear relapse in a sex-dependent manner.

PubMed

Bouchet, Courtney A; Lloyd, Brian A; Loetz, Esteban C; Farmer, Caroline E; Ostrovskyy, Mykola; Haddad, Natalie; Foright, Rebecca M; Greenwood, Benjamin N

2017-08-01

Fear extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear extinction memories are labile and fear tends to return even after successful extinction. The relapse of fear contributes to the poor long-term efficacy of exposure therapy. A single session of voluntary exercise can enhance the acquisition and consolidation of fear extinction in male rats, but the effects of exercise on relapse of fear after extinction are not well understood. Here, we characterized the effects of 2 h of voluntary exercise during the consolidation phase of contextual or auditory fear extinction learning on long-term fear extinction memory and renewal in adult, male and female, Long-Evans rats. Results indicate that exercise enhances consolidation of fear extinction memory and reduces fear relapse after extinction in a sex-dependent manner. These data suggest that brief bouts of exercise could be used as an augmentation strategy for exposure therapy, even in previously sedentary subjects. Fear memories of discrete cues, rather than of contextual ones, may be most susceptible to exercise-augmented extinction, especially in males. Additionally, exercise seems to have the biggest impact on fear relapse phenomena, even if fear extinction memories themselves are only minimally enhanced. © 2017 Bouchet et al.; Published by Cold Spring Harbor Laboratory Press.

Orexin A Differentially Influences the Extinction Retention of Recent and Remote Fear Memory.

PubMed

Shi, Le; Chen, Wenhao; Deng, Jiahui; Chen, Sijing; Han, Ying; Khan, Muhammad Z; Liu, Jiajia; Que, Jianyu; Bao, Yanping; Lu, Lin; Shi, Jie

2018-01-01

Recently the role of the orexin system in the learning and memory, especially orexin A, which could enhance fear memory through regulating the activity of amygdala, has drawn considerable attention. However, the relationship between orexin A and extinction memory remains unclear. To investigate the effect of orexin A on extinction memory in humans, we recruited 43 male subjects and divided them into a recent group and remote group. After acquiring Pavlovian fear conditioning, individuals in recent group experienced fear extinction 24 h after acquisition, and remote group underwent extinction 2 weeks later. Meanwhile, plasma orexin A levels before extinction were measured by enzyme-linked immunosorbent assay. Both groups received memory test 24 h after fear extinction. The results showed that both recent and remote groups successfully acquired fear conditioning and had spontaneous recovery at test. In particular, the correlational analysis indicated that orexin A levels before extinction were negatively associated with fear responses during test only in recent group, but not in remote group. Moreover, individuals with high orexin A levels still kept low fear responses after extinction in recent group by subgroup analyses. The results suggest that orexin A could influence the retention of recent fear memory extinction, without affecting remote fear extinction. These findings remind us the orexin system can be a potential treatment target for fear-related disorders, and the mechanisms of recent and remote fear extinction may be different.

Extinction and Renewal of Conditioned Sexual Responses

PubMed Central

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Both, Stephanie

2014-01-01

Introduction Extinction involves an inhibitory form of new learning that is highly dependent on the context for expression. This is supported by phenomena such as renewal and spontaneous recovery, which may help explain the persistence of appetitive behavior, and related problems such as addictions. Research on these phenomena in the sexual domain is lacking, where it may help to explain the persistence of learned sexual responses. Method Men (n = 40) and women (n = 62) participated in a differential conditioning paradigm, with genital vibrotactile stimulation as US and neutral pictures as conditional stimuli (CSs). Dependent variables were genital and subjective sexual arousal, affect, US expectancy, and approach and avoid tendencies towards the CSs. Extinction and renewal of conditioned sexual responses were studied by context manipulation (AAA vs. ABA condition). Results No renewal effect of genital conditioned responding could be detected, but an obvious recovery of US expectancy following a context change after extinction (ABA) was demonstrated. Additionally, women demonstrated recovery of subjective affect and subjective sexual arousal. Participants in the ABA demonstrated more approach biases towards stimuli. Conclusions The findings support the context dependency of extinction and renewal of conditioned sexual responses in humans. This knowledge may have implications for the treatment of disturbances in sexual appetitive responses such as hypo- and hypersexuality. PMID:25170909

Extinction and renewal of conditioned sexual responses.

PubMed

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Both, Stephanie

2014-01-01

Extinction involves an inhibitory form of new learning that is highly dependent on the context for expression. This is supported by phenomena such as renewal and spontaneous recovery, which may help explain the persistence of appetitive behavior, and related problems such as addictions. Research on these phenomena in the sexual domain is lacking, where it may help to explain the persistence of learned sexual responses. Men (n = 40) and women (n = 62) participated in a differential conditioning paradigm, with genital vibrotactile stimulation as US and neutral pictures as conditional stimuli (CSs). Dependent variables were genital and subjective sexual arousal, affect, US expectancy, and approach and avoid tendencies towards the CSs. Extinction and renewal of conditioned sexual responses were studied by context manipulation (AAA vs. ABA condition). No renewal effect of genital conditioned responding could be detected, but an obvious recovery of US expectancy following a context change after extinction (ABA) was demonstrated. Additionally, women demonstrated recovery of subjective affect and subjective sexual arousal. Participants in the ABA demonstrated more approach biases towards stimuli. The findings support the context dependency of extinction and renewal of conditioned sexual responses in humans. This knowledge may have implications for the treatment of disturbances in sexual appetitive responses such as hypo- and hypersexuality.

Learning deficits expressed as delayed extinction of a conditioned running response following perinatal exposure to vinclozolin.

PubMed

André, Susan M; Markowski, Vincent P

2006-01-01

Vinclozolin (Vz) is one member of a group of fungicides whose metabolites are androgen receptor antagonists. These fungicides have been shown to block androgen-driven development and compromise reproductive function. The current study sought to determine if Vz also affects learning following exposure to low doses during the perinatal period. To test this, an androgen-dependent behavior was examined, the extinction of a previously reinforced running response. Pregnant Long-Evans rats were administered a daily oral dose of 0, 1.5, 3, 6 or 12 mg/kg Vz from the 14th day of gestation through postnatal day 3. After reaching adulthood, male and female offspring were trained to run through a short alleyway for food reinforcement. Acquisition of the response was not affected by Vz exposure. However, males required more trials than females for response extinction once food was no longer available in the apparatus. Males exposed to 6 or 12 mg/kg Vz failed to show any extinction by the end of the procedure, while the lowest dose of Vz appeared to facilitate extinction in both male and female offspring. These results demonstrate that endocrine disrupting antiandrogens can alter nervous system development in addition to the reproductive system.

Cognitive enhancers for facilitating drug cue extinction: insights from animal models.

PubMed

Nic Dhonnchadha, Bríd Áine; Kantak, Kathleen M

2011-08-01

Given the success of cue exposure (extinction) therapy combined with a cognitive enhancer for reducing anxiety, it is anticipated that this approach will prove more efficacious than exposure therapy alone in preventing relapse in individuals with substance use disorders. Several factors may undermine the efficacy of exposure therapy for substance use disorders, but we suspect that neurocognitive impairments associated with chronic drug use are an important contributing factor. Numerous insights on these issues are gained from research using animal models of addiction. In this review, the relationship between brain sites whose learning, memory and executive functions are impaired by chronic drug use and brain sites that are important for effective drug cue extinction learning is explored first. This is followed by an overview of animal research showing improved treatment outcome for drug addiction (e.g. alcohol, amphetamine, cocaine, heroin) when explicit extinction training is conducted in combination with acute dosing of a cognitive-enhancing drug. The mechanism by which cognitive enhancers are thought to exert their benefits is by facilitating consolidation of drug cue extinction memory after activation of glutamatergic receptors. Based on the encouraging work in animals, factors that may be important for the treatment of drug addiction are considered. Copyright © 2011. Published by Elsevier Inc.

Anatomical physiology of spatial extinction.

PubMed

Ciçek, Metehan; Gitelman, Darren; Hurley, Robert S E; Nobre, Anna; Mesulam, Marsel

2007-12-01

Neurologically intact volunteers participated in a functional magnetic resonance imaging experiment that simulated the unilateral (focal) and bilateral (global) stimulations used to elicit extinction in patients with hemispatial neglect. In peristriate areas, attentional modulations were selectively sensitive to contralaterally directed attention. A higher level of mapping was observed in the intraparietal sulcus (IPS), inferior parietal lobule (IPL), and inferior frontal gyrus (IFG). In these areas, there was no distinction between contralateral and ipsilateral focal attention, and the need to distribute attention globally led to greater activity than either focal condition. These physiological characteristics were symmetrically distributed in the IPS and IFG, suggesting that the effects of unilateral lesions in these 2 areas can be compensated by the contralateral hemisphere. In the IPL, the greater activation by the bilateral attentional mode was seen only in the right hemisphere. Its contralateral counterpart displayed equivalent activations when attention was distributed to the right, to the left, or bilaterally. Within the context of this experiment, the IPL of the right hemisphere emerged as the one area where unilateral lesions can cause the most uncompensated and selective impairment of global attention (without interfering with unilateral attention to either side), giving rise to the phenomenon of extinction.

Extinction, Spontaneous Recovery and Renewal of Flavor Preferences Based on Taste-Taste Learning

ERIC Educational Resources Information Center

Diaz, Estrella; De la Casa, L. G.

2011-01-01

This paper presents evidence of extinction, spontaneous recovery and renewal in a conditioned preferences paradigm based on taste-taste associations. More specifically, in three experiments rats exposed to a simultaneous compound of citric acid-saccharin solution showed a preference for the citric solution when the preference was measured with a…

Last Words: The Dying of Languages.

ERIC Educational Resources Information Center

Sampat, Payal

2001-01-01

Discusses the problem of language extinction as cultural homogeneity spreads over the earth. Just 600 of the world's 6,800 languages are safe from extinction meaning that they are still being learned by children. Many anthropologists see the decline as analogous to biodiversity loss: it is a form of cultural impoverishment and a loss of our…

Violation of eating expectancies does not reduce conditioned desires for chocolate.

PubMed

van den Akker, Karolien; van den Broek, Myrr; Havermans, Remco C; Jansen, Anita

2016-05-01

Although eating desires can be easily learned, their extinction appears more difficult. The present two-session study aimed to investigate the role of eating expectancies in the short and longer-term extinction of eating desires. In addition, the relationship between eating desires and conditioned evaluations was examined to test whether they might share a similar mechanism. It was hypothesized that the short-term extinction of eating desires would be more successful after the disconfirmation of eating expectancies (instructed extinction or IE), while resulting in worse longer-term extinction because omission of the food reward during extinction is not surprising. In contrast to the hypotheses, it was found that IE had no effect on the short-term and longer-term extinction of eating desires. Eating desires correlated with conditioned evaluations only to some extent. It is concluded that eating expectancies do not mediate the short-term extinction of conditioned eating desires. In addition, their longer-term extinction does not appear to be facilitated by a greater violation of eating expectancies. This suggests that it might not be necessary to focus on expectancy violation in cue exposure therapy to reduce eating desires. Copyright © 2016 Elsevier Ltd. All rights reserved.

Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear

PubMed Central

Rodriguez-Romaguera, Jose; Do Monte, Fabricio H. M.; Quirk, Gregory J.

2012-01-01

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces symptoms of intractable obsessive-compulsive disorder (OCD), but the mechanism of action is unknown. OCD is characterized by avoidance behaviors that fail to extinguish, and DBS could act, in part, by facilitating extinction of fear. We investigated this possibility by using auditory fear conditioning in rats, for which the circuits of fear extinction are well characterized. We found that DBS of the VS (the VC/VS homolog in rats) during extinction training reduced fear expression and strengthened extinction memory. Facilitation of extinction was observed for a specific zone of dorsomedial VS, just above the anterior commissure; stimulation of more ventrolateral sites in VS impaired extinction. DBS effects could not be obtained with pharmacological inactivation of either dorsomedial VS or ventrolateral VS, suggesting an extrastriatal mechanism. Accordingly, DBS of dorsomedial VS (but not ventrolateral VS) increased expression of a plasticity marker in the prelimbic and infralimbic prefrontal cortices, the orbitofrontal cortex, the amygdala central nucleus (lateral division), and intercalated cells, areas known to learn and express extinction. Facilitation of fear extinction suggests that, in accord with clinical observations, DBS could augment the effectiveness of cognitive behavioral therapies for OCD. PMID:22586125

Intact implicit learning in autism spectrum conditions.

PubMed

Brown, Jamie; Aczel, Balazs; Jiménez, Luis; Kaufman, Scott Barry; Grant, Kate Plaisted

2010-09-01

Individuals with autism spectrum condition (ASC) have diagnostic impairments in skills that are associated with an implicit acquisition; however, it is not clear whether ASC individuals show specific implicit learning deficits. We compared ASC and typically developing (TD) individuals matched for IQ on five learning tasks: four implicit learning tasks--contextual cueing, serial reaction time, artificial grammar learning, and probabilistic classification learning tasks--that used procedures expressly designed to minimize the use of explicit strategies, and one comparison explicit learning task, paired associates learning. We found implicit learning to be intact in ASC. Beyond no evidence of differences, there was evidence of statistical equivalence between the groups on all the implicit learning tasks. This was not a consequence of compensation by explicit learning ability or IQ. Furthermore, there was no evidence to relate implicit learning to ASC symptomatology. We conclude that implicit mechanisms are preserved in ASC and propose that it is disruption by other atypical processes that impact negatively on the development of skills associated with an implicit acquisition.

[Extinction and Reconsolidation of Memory].

PubMed

Zuzina, A B; Balaban, P M

2015-01-01

Retrieval of memory followed by reconsolidation can strengthen a memory, while retrieval followed by extinction results in a decrease of memory performance due to weakening of existing memory or formation of a competing memory. In our study we analyzed the behavior and responses of identified neurons involved in the network underlying aversive learning in terrestrial snail Helix, and made an attempt to describe the conditions in which the retrieval of memory leads either to extinction or reconsolidation. In the network underlying the withdrawal behavior, sensory neurons, premotor interneurons, motor neurons, and modulatory for this network serotonergic neurons are identified and recordings from representatives of these groups were made before and after aversive learning. In the network underlying feeding behavior, the premotor modulatory serotonergic interneurons and motor neurons involved in motor program of feeding are identified. Analysis of changes in neural activity after aversive learning showed that modulatory neurons of feeding behavior do not demonstrate any changes (sometimes a decrease of responses to food was observed), while responses to food in withdrawal behavior premotor interneurons changed qualitatively, from under threshold EPSPs to spike discharges. Using a specific for serotonergic neurons neurotoxin 5,7-DiHT it was shown previously that the serotonergic system is necessary for the aversive learning, but is not necessary for maintenance and retrieval of this memory. These results suggest that the serotonergic neurons that are necessary as part of a reinforcement for developing the associative changes in the network may be not necessary for the retrieval of memory. The hypothesis presented in this review concerns the activity of the "reinforcement" serotonergic neurons that is suggested to be the gate condition for the choice between extinction/reconsolidation triggered by memory retrieval: if these serotonergic neurons do not respond during the retrieval due to adaptation, habituation, changes in environment, etc., then we will observe the extinction; while if these neurons respond to the CS during memory retrieval, we will observe the reconsolidation phenomenon.

Unconscious Familiarity-based Color-Form Binding: Evidence from Visual Extinction.

PubMed

Rappaport, Sarah J; Riddoch, M Jane; Chechlacz, Magda; Humphreys, Glyn W

2016-03-01

There is good evidence that early visual processing involves the coding of different features in independent brain regions. A major question, then, is how we see the world in an integrated manner, in which the different features are "bound" together. A standard account of this has been that feature binding depends on attention to the stimulus, which enables only the relevant features to be linked together [Treisman, A., & Gelade, G. A feature-integration theory of attention. Cognitive Psychology, 12, 97-136, 1980]. Here we test this influential idea by examining whether, in patients showing visual extinction, the processing of otherwise unconscious (extinguished) stimuli is modulated by presenting objects in their correct (familiar) color. Correctly colored objects showed reduced extinction when they had a learned color, and this color matched across the ipsi- and contralesional items (red strawberry + red tomato). In contrast, there was no reduction in extinction under the same conditions when the stimuli were colored incorrectly (blue strawberry + blue tomato; Experiment 1). The result was not due to the speeded identification of a correctly colored ipsilesional item, as there was no benefit from having correctly colored objects in different colors (red strawberry + yellow lemon; Experiment 2). There was also no benefit to extinction from presenting the correct colors in the background of each item (Experiment 3). The data suggest that learned color-form binding can reduce extinction even when color is irrelevant for the task. The result is consistent with preattentive binding of color and shape for familiar stimuli.

Neural circuitry of abdominal pain-related fear learning and reinstatement in irritable bowel syndrome.

PubMed

Icenhour, A; Langhorst, J; Benson, S; Schlamann, M; Hampel, S; Engler, H; Forsting, M; Elsenbruch, S

2015-01-01

Altered pain anticipation likely contributes to disturbed central pain processing in chronic pain conditions like irritable bowel syndrome (IBS), but the learning processes shaping the expectation of pain remain poorly understood. We assessed the neural circuitry mediating the formation, extinction, and reactivation of abdominal pain-related memories in IBS patients compared to healthy controls (HC) in a differential fear conditioning paradigm. During fear acquisition, predictive visual cues (CS(+)) were paired with rectal distensions (US), while control cues (CS(-)) were presented unpaired. During extinction, only CSs were presented. Subsequently, memory reactivation was assessed with a reinstatement procedure involving unexpected USs. Using functional magnetic resonance imaging, group differences in neural activation to CS(+) vs CS(-) were analyzed, along with skin conductance responses (SCR), CS valence, CS-US contingency, state anxiety, salivary cortisol, and alpha-amylase activity. The contribution of anxiety symptoms was addressed in covariance analyses. Fear acquisition was altered in IBS, as indicated by more accurate contingency awareness, greater CS-related valence change, and enhanced CS(+)-induced differential activation of prefrontal cortex and amygdala. IBS patients further revealed enhanced differential cingulate activation during extinction and greater differential hippocampal activation during reinstatement. Anxiety affected neural responses during memory formation and reinstatement. Abdominal pain-related fear learning and memory processes are altered in IBS, mediated by amygdala, cingulate cortex, prefrontal areas, and hippocampus. Enhanced reinstatement may contribute to hypervigilance and central pain amplification, especially in anxious patients. Preventing a 'relapse' of learned fear utilizing extinction-based interventions may be a promising treatment goal in IBS. © 2014 John Wiley & Sons Ltd.

Implicit Perceptual-Motor Skill Learning in Mild Cognitive Impairment and Parkinson's Disease

PubMed Central

Gobel, Eric W.; Blomeke, Kelsey; Zadikoff, Cindy; Simuni, Tanya; Weintraub, Sandy; Reber, Paul J.

2015-01-01

Objective Implicit skill learning is hypothesized to depend on nondeclarative memory that operates independent of the medial temporal lobe (MTL) memory system and instead depends on cortico-striatal circuits between the basal ganglia and cortical areas supporting motor function and planning. Research with the Serial Reaction Time (SRT) task suggests that patients with memory-disorders due to MTL damage exhibit normal implicit sequence learning. However, reports of intact learning rely on observations of no group differences, leading to speculation whether implicit sequence learning is fully intact in these patients. Patients with Parkinson's Disease (PD) often exhibit impaired sequence learning, but this impairment is not universally observed. Method Implicit perceptual-motor sequence learning was examined using the Serial Interception Sequence Learning (SISL) task in patients with amnestic Mild Cognitive Impairment (MCI; n=11) and patients with PD (n=15). Sequence learning in SISL is resistant to explicit learning and individually adapted task difficulty controls for baseline performance differences. Results Patients with MCI exhibited robust sequence learning, equivalent to healthy older adults (n=20), supporting the hypothesis that the MTL does not contribute to learning in this task. In contrast, the majority of patients with PD exhibited no sequence-specific learning in spite of matched overall task performance. Two patients with PD exhibited performance indicative of an explicit compensatory strategy suggesting that impaired implicit learning may lead to greater reliance on explicit memory in some individuals. Conclusion The differences in learning between patient groups provides strong evidence in favor of implicit sequence learning depending solely on intact basal ganglia function with no contribution from the MTL memory system. PMID:23688213

Neural correlates of appetitive extinction in humans

PubMed Central

Tapia León, Isabell; Stark, Rudolf; Klucken, Tim

2017-01-01

Abstract Appetitive extinction receives attention as an important model for the treatment of psychiatric disorders. However, in humans, its underlying neural correlates remain unknown. To close this gap, we investigated appetitive acquisition and extinction with fMRI in a 2-day monetary incentive delay paradigm. During appetitive conditioning, one stimulus (CS+) was paired with monetary reward, while another stimulus (CS−) was never rewarded. Twenty-four hours later, subjects underwent extinction, in which neither CS was reinforced. Appetitive conditioning elicited stronger skin conductance responses to the CS+ as compared with the CS−. Regarding subjective ratings, the CS+ was rated more pleasant and arousing than the CS− after conditioning. Furthermore, fMRI-results (CS+ − CS−) showed activation of the reward circuitry including amygdala, midbrain and striatal areas. During extinction, conditioned responses were successfully extinguished. In the early phase of extinction, we found a significant activation of the caudate, the hippocampus, the dorsal and ventral anterior cingulate cortex (dACC and vACC). In the late phase, we found significant activation of the nucleus accumbens (NAcc) and the amygdala. Correlational analyses with subjective ratings linked extinction success to the vACC and the NAcc, while associating the dACC with reduced extinction. The results reveal neural correlates of appetitive extinction in humans and extend assumptions from models for human extinction learning. PMID:27803289

Evidence for the involvement of extinction-associated inhibitory learning in the forced swimming test.

PubMed

Campus, P; Colelli, V; Orsini, C; Sarra, D; Cabib, S

2015-02-01

The forced swimming test (FST) remains one of the most used tools for screening antidepressants in rodent models. Nonetheless, the nature of immobility, its main behavioral measure, is still a matter of debate. The present study took advantage of our recent finding that mice of the inbred DBA/2J strain require a functioning left dorsolateral striatum (DLS) to consolidate long-term memory of FST to test whether immobility is the outcome of stress-related learning. Infusion of the GABA-A agonist muscimol in the left DLS immediately after a single experience of FST prevented and infusion in the left or the right amygdala impaired recall of the acquired levels of immobility in a probe test performed 24h later. Post-training left DLS infusion of muscimol, at a dose capable of preventing retention of FST-induced immobility, did not influence 24h retention of inhibitory avoidance training or of the escape response acquired in a water T-maze. However, this same treatment prevented 24h retention of the extinction training of the consolidated escape response. These results indicate that a left DLS-centered memory system selectively mediates memory consolidation of FST and of escape extinction and support the hypothesis that immobility is the result of extinction-like inhibitory learning involving all available escape responses due to the inescapable/unavoidable nature of FST experience. Copyright © 2014 Elsevier B.V. All rights reserved.

Low-Cost Avoidance Behaviors are Resistant to Fear Extinction in Humans

PubMed Central

Vervliet, Bram; Indekeu, Ellen

2015-01-01

Elevated levels of fear and avoidance are core symptoms across the anxiety disorders. It has long been known that fear serves to motivate avoidance. Consequently, fear extinction has been the primary focus in pre-clinical anxiety research for decades, under the implicit assumption that removing the motivator of avoidance (fear) would automatically mitigate the avoidance behaviors as well. Although this assumption has intuitive appeal, it has received little scientific scrutiny. The scarce evidence from animal studies is mixed, while the assumption remains untested in humans. The current study applied an avoidance conditioning protocol in humans to investigate the effects of fear extinction on the persistence of low-cost avoidance. Online danger-safety ratings and skin conductance responses documented the dynamics of conditioned fear across avoidance and extinction phases. Anxiety- and avoidance-related questionnaires explored individual differences in rates of avoidance. Participants first learned to click a button during a predictive danger signal, in order to cancel an upcoming aversive electrical shock (avoidance conditioning). Next, fear extinction was induced by presenting the signal in the absence of shocks while button-clicks were prevented (by removing the button in Experiment 1, or by instructing not to click the button in Experiment 2). Most importantly, post-extinction availability of the button caused a significant return of avoidant button-clicks. In addition, trait-anxiety levels correlated positively with rates of avoidance during a predictive safety signal, and with the rate of pre- to post-extinction decrease during this signal. Fear measures gradually decreased during avoidance conditioning, as participants learned that button-clicks effectively canceled the shock. Preventing button-clicks elicited a sharp increase in fear, which subsequently extinguished. Fear remained low during avoidance testing, but danger-safety ratings increased again when button-clicks were subsequently prevented. Together, these results show that low-cost avoidance behaviors can persist following fear extinction and induce increased threat appraisal. On the other hand, fear extinction did reduce augmented rates of unnecessary avoidance during safety in trait-anxious individuals, and instruction-based response prevention was more effective than removal of response cues. More research is needed to characterize the conditions under which fear extinction might mitigate avoidance. PMID:26733837

Maximizing Exposure Therapy: An Inhibitory Learning Approach

PubMed Central

Craske, Michelle G.; Treanor, Michael; Conway, Chris; Zbozinek, Tomislav; Vervliet, Bram

2014-01-01

Exposure therapy is an effective approach for treating anxiety disorders, although a substantial number of individuals fail to benefit or experience a return of fear after treatment. Research suggests that anxious individuals show deficits in the mechanisms believed to underlie exposure therapy, such as inhibitory learning. Targeting these processes may help improve the efficacy of exposure-based procedures. Although evidence supports an inhibitory learning model of extinction, there has been little discussion of how to implement this model in clinical practice. The primary aim of this paper is to provide examples to clinicians for how to apply this model to optimize exposure therapy with anxious clients, in ways that distinguish it from a ‘fear habituation’ approach and ‘belief disconfirmation’ approach within standard cognitive-behavior therapy. Exposure optimization strategies include 1) expectancy violation, 2) deepened extinction, 3) occasional reinforced extinction, 4) removal of safety signals, 5) variability, 6) retrieval cues, 7) multiple contexts, and 8) affect labeling. Case studies illustrate methods of applying these techniques with a variety of anxiety disorders, including obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, specific phobia, and panic disorder. PMID:24864005

Effects of postnatal malnutrition and senescence on learning, long-term memory, and extinction in the rat.

PubMed

Martínez, Yvonne; Díaz-Cintra, Sofía; León-Jacinto, Uriel; Aguilar-Vázquez, Azucena; Medina, Andrea C; Quirarte, Gina L; Prado-Alcalá, Roberto A

2009-10-12

There is a wealth of information indicating that the hippocampal formation is important for learning and memory consolidation. The hippocampus is very sensitive to ageing and developmentally stressful factors such as prenatal malnutrition, which produces anatomical alterations of hippocampal pyramidal cells as well as impaired spatial learning. On the other hand, there are no reports about differential effects of postnatal malnutrition, installed at birth and maintained all through life in young and aged rats, on learning and memory of active avoidance, a task with an important procedural component. We now report that learning and long-term retention of this task were impaired in young malnourished animals, but not in young control, senile control, and senile malnourished Sprague-Dawley rats; young and senile rats were 90 and 660 days of age, respectively. Extinction tests showed, however, that long-term memory of the malnourished groups and senile control animals is impaired as compared with the young control animals. These data strongly suggest that the learning and long-term retention impairments seen in the young animals were due to postnatal malnutrition; in the senile groups, this cognitive alteration did not occur, probably because ageing itself is an important factor that enables the brain to engage in compensatory mechanisms that reduce the effects of malnutrition. Nonetheless, ageing and malnutrition, conditions known to produce anatomic and functional hippocampal alterations, impede the maintenance of long-term memory, as seen during the extinction test.

Fear conditioning and extinction across development: evidence from human studies and animal models.

PubMed

Shechner, Tomer; Hong, Melanie; Britton, Jennifer C; Pine, Daniel S; Fox, Nathan A

2014-07-01

The ability to differentiate danger and safety through associative processes emerges early in life. Understanding the mechanisms underlying associative learning of threat and safety can clarify the processes that shape development of normative fears and pathological anxiety. Considerable research has used fear conditioning and extinction paradigms to delineate underlying mechanisms in animals and human adults; however, little is known about these mechanisms in children and adolescents. The current paper summarizes the empirical data on the development of fear conditioning and extinction. It reviews methodological considerations and future directions for research on fear conditioning and extinction in pediatric populations. Copyright © 2014 Elsevier B.V. All rights reserved.

HDAC inhibitors as cognitive enhancers in fear, anxiety and trauma therapy: where do we stand?

PubMed Central

Whittle, Nigel; Singewald, Nicolas

2014-01-01

A novel strategy to treat anxiety and fear-related disorders such as phobias, panic and PTSD (post-traumatic stress disorder) is combining CBT (cognitive behavioural therapy), including extinction-based exposure therapy, with cognitive enhancers. By targeting and boosting mechanisms underlying learning, drug development in this field aims at designing CBT-augmenting compounds that help to overcome extinction learning deficits, promote long-term fear inhibition and thus support relapse prevention. Progress in revealing the role of epigenetic regulation of specific genes associated with extinction memory generation has opened new avenues in this direction. The present review examines recent evidence from pre-clinical studies showing that increasing histone acetylation, either via genetic or pharmacological inhibition of HDACs (histone deacetylases) by e.g. vorinostat/SAHA (suberoylanilide hydroxamic acid), entinostat/MS-275, sodium butyrate, TSA (trichostatin A) or VPA (valproic acid), or by targeting HATs (histone acetyltransferases), augments fear extinction and, importantly, generates a long-term extinction memory that can protect from return of fear phenomena. The molecular mechanisms and pathways involved including BDNF (brain-derived neurotrophic factor) and NMDA (N-methyl-D-aspartate) receptor signalling are just beginning to be revealed. First studies in healthy humans are in support of extinction-facilitating effects of HDAC inhibitors. Very recent evidence that HDAC inhibitors can rescue deficits in extinction-memory-impaired rodents indicates a potential clinical utility of this approach also for exposure therapy-resistant patients. Important future work includes investigation of the long-term safety aspects of HDAC inhibitor treatment, as well as design of isotype(s)-specific inhibitors. Taken together, HDAC inhibitors display promising potential as pharmacological adjuncts to augment the efficacy of exposure-based approaches in anxiety and trauma therapy. PMID:24646280

Separation of Time-Based and Trial-Based Accounts of the Partial Reinforcement Extinction Effect

PubMed Central

Bouton, Mark E.; Woods, Amanda M.; Todd, Travis P.

2013-01-01

Two appetitive conditioning experiments with rats examined time-based and trial-based accounts of the partial reinforcement extinction effect (PREE). In the PREE, the loss of responding that occurs in extinction is slower when the conditioned stimulus (CS) has been paired with a reinforcer on some of its presentations (partially reinforced) instead of every presentation (continuously reinforced). According to a time-based or “time-accumulation” view (e.g., Gallistel & Gibbon, 2000), the PREE occurs because the organism has learned in partial reinforcement to expect the reinforcer after a larger amount of time has accumulated in the CS over trials. In contrast, according to a trial-based view (e.g., Capaldi, 1967), the PREE occurs because the organism has learned in partial reinforcement to expect the reinforcer after a larger number of CS presentations. Experiment 1 used a procedure that equated partially- and continuously-reinforced groups on their expected times to reinforcement during conditioning. A PREE was still observed. Experiment 2 then used an extinction procedure that allowed time in the CS and the number of trials to accumulate differentially through extinction. The PREE was still evident when responding was examined as a function of expected time units to the reinforcer, but was eliminated when responding was examined as a function of expected trial units to the reinforcer. There was no evidence that the animal responded according to the ratio of time accumulated during the CS in extinction over the time in the CS expected before the reinforcer. The results thus favor a trial-based account over a time-based account of extinction and the PREE. PMID:23962669

Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons

PubMed Central

Maroun, Mouna; Ioannides, Pericles J.; Bergman, Krista L.; Kavushansky, Alexandra; Holmes, Andrew; Wellman, Cara L.

2013-01-01

Stress-sensitive psychopathologies such as post-traumatic stress disorder are characterized by deficits in fear extinction and dysfunction of corticolimbic circuits mediating extinction. Chronic stress facilitates fear conditioning, impairs extinction, and produces dendritic proliferation in the basolateral amygdala (BLA), a critical site of plasticity for extinction. Acute stress impairs extinction, alters plasticity in the medial prefrontal cortex-to-BLA circuit, and causes dendritic retraction in the medial prefrontal cortex. Here, we examined extinction learning and basolateral amygdala pyramidal neuron morphology in adult male rats following a single elevated platform stress. Acute stress impaired extinction acquisition and memory, and produced dendritic retraction and increased mushroom spine density in basolateral amygdala neurons in the right hemisphere. Unexpectedly, irrespective of stress, rats that underwent fear and extinction testing showed basolateral amygdala dendritic retraction and altered spine density relative to non-conditioned rats, particularly in the left hemisphere. Thus, extinction deficits produced by acute stress are associated with increased spine density and dendritic retraction in basolateral amygdala pyramidal neurons. Furthermore, the finding that conditioning and extinction as such was sufficient to alter basolateral amygdala morphology and spine density illustrates the sensitivity of basolateral amygdala morphology to behavioral manipulation. These findings may have implications for elucidating the role of the amygdala in the pathophysiology of stress-related disorders. PMID:23714419

Contextual-specificity of short-delay extinction in humans: Renewal of fear-potentiated startle in a virtual environment

PubMed Central

Alvarez, Ruben P.; Johnson, Linda; Grillon, Christian

2007-01-01

A recent fear-potentiated startle study in rodents suggested that extinction was not context dependent when extinction was conducted after a short delay following acquisition, suggesting that extinction can lead to erasure of fear learning in some circumstances. The main objective of this study was to attempt to replicate these findings in humans by examining the context specificity of short-delay extinction in an ABA renewal procedure using virtual reality environments. A second objective was to examine whether renewal, if any, would be influenced by context conditioning. Subjects underwent differential aversive conditioning in virtual context A, which was immediately followed by extinction in virtual context B. Extinction was followed by tests of renewal in context A and B, with the order counterbalanced across subjects. Results showed that extinction was context dependent. Evidence for renewal was established using fear-potentiated startle as well as skin conductance and fear ratings. In addition, although contextual anxiety was greater in the acquisition context than in the extinction context during renewal, as assessed with startle, context conditioning did not influence the renewal effect. These data do not support the view that extinction conducted shortly after acquisition is context independent. Hence, they do not provide evidence that extinction can lead to erasure of a fear memory established via Pavlovian conditioning. PMID:17412963

Interactions between radiation and amphetamine in taste-aversion learning and the role of the area postrema in amphetamine-induced conditioned taste aversions

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rabin, B.M.; Hunt, W.A.; Lee, J.

1987-01-01

Three experiments were run to assess the role of the area postrema in taste-aversion learning resulting from combined treatment with subthreshold unconditioned stimuli and in the acquisition of an amphetamine-induced taste aversion. In the first experiment, it was shown that combined treatment with subthreshold radiation (15 rad) and subthreshold amphetamine (0.5 mg/kg, IP) resulted in the acquisition of a taste aversion. The second experiment showed that lesions of the area postrema blocked taste aversion learning produced by two subthreshold doses of amphetamine. In the third experiment, which looked at the dose-response curve for amphetamine-induced taste aversion learning to intact ratsmore » and rats with area postrema lesions, it was shown that both groups of rats acquired taste aversions following injection of amphetamine, although the rats with lesions showed a less-severe aversion than the intact rats. The results are interpreted as indicating that amphetamine-induced taste-aversion learning may involve area post-remamediated mechanisms, particularly at the lower doses, but an intact area postrema is not a necessary condition of the acquisition of an amphetamine-induced taste aversion.« less

Vagus Nerve Stimulation Reduces Cocaine Seeking and Alters Plasticity in the Extinction Network

ERIC Educational Resources Information Center

Childs, Jessica E.; DeLeon, Jaime; Nickel, Emily; Kroener, Sven

2017-01-01

Drugs of abuse cause changes in the prefrontal cortex (PFC) and associated regions that impair inhibitory control over drug-seeking. Breaking the contingencies between drug-associated cues and the delivery of the reward during extinction learning reduces rates of relapse. Here we used vagus nerve stimulation (VNS) to induce targeted synaptic…

A Unifying Model of the Role of the Infralimbic Cortex in Extinction and Habits

ERIC Educational Resources Information Center

Barker, Jacqueline M.; Taylor, Jane R.; Chandler, L. Judson

2014-01-01

The infralimbic prefrontal cortex (IL) has been shown to be critical for the regulation of flexible behavior, but its precise function remains unclear. This region has been shown to be critical for the acquisition, consolidation, and expression of extinction learning, leading many to hypothesize that IL suppresses behavior as part of a…

The Histone Deacetylase Inhibitor Valproic Acid Enhances Acquisition, Extinction, and Reconsolidation of Conditioned Fear

ERIC Educational Resources Information Center

Bredy, Timothy W.; Barad, Mark

2008-01-01

Histone modifications contribute to the epigenetic regulation of gene expression, a process now recognized to be important for the consolidation of long-term memory. Valproic acid (VPA), used for many years as an anticonvulsant and a mood stabilizer, has effects on learning and memory and enhances the extinction of conditioned fear through its…

Orexin A Differentially Influences the Extinction Retention of Recent and Remote Fear Memory

PubMed Central

Shi, Le; Chen, Wenhao; Deng, Jiahui; Chen, Sijing; Han, Ying; Khan, Muhammad Z.; Liu, Jiajia; Que, Jianyu; Bao, Yanping; Lu, Lin; Shi, Jie

2018-01-01

Recently the role of the orexin system in the learning and memory, especially orexin A, which could enhance fear memory through regulating the activity of amygdala, has drawn considerable attention. However, the relationship between orexin A and extinction memory remains unclear. To investigate the effect of orexin A on extinction memory in humans, we recruited 43 male subjects and divided them into a recent group and remote group. After acquiring Pavlovian fear conditioning, individuals in recent group experienced fear extinction 24 h after acquisition, and remote group underwent extinction 2 weeks later. Meanwhile, plasma orexin A levels before extinction were measured by enzyme-linked immunosorbent assay. Both groups received memory test 24 h after fear extinction. The results showed that both recent and remote groups successfully acquired fear conditioning and had spontaneous recovery at test. In particular, the correlational analysis indicated that orexin A levels before extinction were negatively associated with fear responses during test only in recent group, but not in remote group. Moreover, individuals with high orexin A levels still kept low fear responses after extinction in recent group by subgroup analyses. The results suggest that orexin A could influence the retention of recent fear memory extinction, without affecting remote fear extinction. These findings remind us the orexin system can be a potential treatment target for fear-related disorders, and the mechanisms of recent and remote fear extinction may be different. PMID:29773974

Duration of the unconditioned stimulus in appetitive conditioning of honeybees differentially impacts learning, long-term memory strength, and the underlying protein synthesis

PubMed Central

Marter, Kathrin; Grauel, M. Katharina; Lewa, Carmen; Morgenstern, Laura; Buckemüller, Christina; Heufelder, Karin; Ganz, Marion

2014-01-01

This study examines the role of stimulus duration in learning and memory formation of honeybees (Apis mellifera). In classical appetitive conditioning honeybees learn the association between an initially neutral, conditioned stimulus (CS) and the occurrence of a meaningful stimulus, the unconditioned stimulus (US). Thereby the CS becomes a predictor for the US eliciting a conditioned response (CR). Here we study the role of US duration in classical conditioning by examining honeybees conditioned with different US durations. We quantify the CR during acquisition, memory retention, and extinction of the early long-term memory (eLTM), and examine the molecular mechanisms of eLTM by interfering with protein synthesis. We find that the US duration affects neither the probability nor the strength of the CR during acquisition, eLTM retention, and extinction 24 h after conditioning. However, we find that the resistance to extinction 24 h after conditioning is susceptible to protein synthesis inhibition depending on the US duration. We conclude that the US duration does not affect the predictability of the US but modulates the protein synthesis underlying the eLTM's strength. Thus, the US duration differentially impacts learning, eLTM strength, and its underlying protein synthesis. PMID:25403456

Physiological and Emotional Reactivity to Learning and Frustration

ERIC Educational Resources Information Center

Lewis, Michael; Hitchcock, Daniel F. A.; Sullivan, Margaret Wolan

2004-01-01

This study examined the behavioral (arm, facial) and autonomic (heart rate, respiratory sinus arrhythmia [RSA], and adrenocortical axis) reactivity of 56 4-month-old infants in response to contingency learning and extinction-induced frustration. During learning, infants displayed increases in operant arm response and positive emotional…

High-Resolution Coproecology: Using Coprolites to Reconstruct the Habits and Habitats of New Zealand’s Extinct Upland Moa (Megalapteryx didinus)

PubMed Central

Wood, Jamie R.; Wilmshurst, Janet M.; Wagstaff, Steven J.; Worthy, Trevor H.; Rawlence, Nicolas J.; Cooper, Alan

2012-01-01

Knowledge about the diet and ecology of extinct herbivores has important implications for understanding the evolution of plant defence structures, establishing the influences of herbivory on past plant community structure and composition, and identifying pollination and seed dispersal syndromes. The flightless ratite moa (Aves: Dinornithiformes) were New Zealand’s largest herbivores prior to their extinction soon after initial human settlement. Here we contribute to the knowledge of moa diet and ecology by reporting the results of a multidisciplinary study of 35 coprolites from a subalpine cave (Euphrates Cave) on the South Island of New Zealand. Ancient DNA analysis and radiocarbon dating revealed the coprolites were deposited by the extinct upland moa (Megalapteryx didinus), and span from at least 6,368±31 until 694±30 14C years BP; the approximate time of their extinction. Using pollen, plant macrofossil, and ancient DNA analyses, we identified at least 67 plant taxa from the coprolites, including the first evidence that moa fed on the nectar-rich flowers of New Zealand flax (Phormium) and tree fuchsia (Fuchsia excorticata). The plant assemblage from the coprolites reflects a highly-generalist feeding ecology for upland moa, including browsing and grazing across the full range of locally available habitats (spanning southern beech (Nothofagus) forest to tussock (Chionochloa) grassland). Intact seeds in the coprolites indicate that upland moa may have been important dispersal agents for several plant taxa. Plant taxa with putative anti-browse adaptations were also identified in the coprolites. Clusters of coprolites (based on pollen assemblages, moa haplotypes, and radiocarbon dates), probably reflect specimens deposited at the same time by individual birds, and reveal the necessity of suitably large sample sizes in coprolite studies to overcome potential biases in diet interpretation. PMID:22768206

Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model

PubMed Central

Whittle, Nigel; Schmuckermair, Claudia; Gunduz Cinar, Ozge; Hauschild, Markus; Ferraguti, Francesco; Holmes, Andrew; Singewald, Nicolas

2013-01-01

Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in S1 mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with d-cycloserine (N-methly-d-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation (DBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled ‘Cognitive Enhancers’. PMID:22722028

Extinction with multiple excitors

PubMed Central

McConnell, Bridget L.; Miguez, Gonzalo; Miller, Ralph R.

2012-01-01

Four conditioned suppression experiments with rats, using an ABC renewal design, investigated the effects of compounding the target conditioned excitor with additional, nontarget conditioned excitors during extinction. Experiment 1 showed stronger extinction, as evidenced by less renewal, when the target excitor was extinguished in compound with a second excitor, relative to when it was extinguished with associatively neutral stimuli. Critically, this deepened extinction effect was attenuated (i.e., more renewal occurred) when a third excitor was added during extinction training. This novel demonstration contradicts the predictions of associative learning models based on total error reduction, but it is explicable in terms of a counteraction effect within the framework of the extended comparator hypothesis. The attenuated deepened extinction effect was replicated in Experiments 2a and 3, which also showed that pretraining consisting of weakening the association between the two additional excitors (Experiments 2a and 2b) or weakening the association between one of the additional excitors and the unconditioned stimulus (Experiment 3) attenuated the counteraction effect, thereby resulting in a decrease in responding to the target excitor. These results suggest that more than simple total error reduction determines responding after extinction. PMID:23055103

Stress and Fear Extinction

PubMed Central

Maren, Stephen; Holmes, Andrew

2016-01-01

Stress has a critical role in the development and expression of many psychiatric disorders, and is a defining feature of posttraumatic stress disorder (PTSD). Stress also limits the efficacy of behavioral therapies aimed at limiting pathological fear, such as exposure therapy. Here we examine emerging evidence that stress impairs recovery from trauma by impairing fear extinction, a form of learning thought to underlie the suppression of trauma-related fear memories. We describe the major structural and functional abnormalities in brain regions that are particularly vulnerable to stress, including the amygdala, prefrontal cortex, and hippocampus, which may underlie stress-induced impairments in extinction. We also discuss some of the stress-induced neurochemical and molecular alterations in these brain regions that are associated with extinction deficits, and the potential for targeting these changes to prevent or reverse impaired extinction. A better understanding of the neurobiological basis of stress effects on extinction promises to yield novel approaches to improving therapeutic outcomes for PTSD and other anxiety and trauma-related disorders. PMID:26105142

A Memory Retrieval-Extinction Procedure to Prevent Drug Craving and Relapse

PubMed Central

Xue, Yan-Xue; Luo, Yi-Xiao; Wu, Ping; Shi, Hai-Shui; Xue, Li-Fen; Chen, Chen; Zhu, Wei-Li; Ding, Zeng-Bo; Bao, Yan-ping; Shi, Jie; Epstein, David H.; Shaham, Yavin; Lu, Lin

2013-01-01

Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence. PMID:22499948

Occasion setting, inhibition, and the contextual control of extinction in Pavlovian and instrumental (operant) learning.

PubMed

Trask, Sydney; Thrailkill, Eric A; Bouton, Mark E

2017-04-01

An occasion setter is a stimulus that modulates the ability of another stimulus to control behavior. A rich history of experimental investigation has identified several important properties that define occasion setters and the conditions that give rise to occasion setting. In this paper, we first consider the basic hallmarks of occasion setting in Pavlovian conditioning. We then review research that has examined the mechanisms underlying the crucial role of context in Pavlovian and instrumental extinction. In Pavlovian extinction, evidence suggests that the extinction context can function as a negative occasion setter whose role is to disambiguate the current meaning of the conditioned stimulus; the conditioning context can also function as a positive occasion setter. In operant extinction, in contrast, the extinction context may directly inhibit the response, and the conditioning context can directly excite it. We outline and discuss the key results supporting these distinctions. Copyright © 2016 Elsevier B.V. All rights reserved.

Blockade of estrogen by hormonal contraceptives impairs fear extinction in female rats and women.

PubMed

Graham, Bronwyn M; Milad, Mohammed R

2013-02-15

Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production; yet, their effects on fear extinction are unknown. We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women (n=76) and female rats (n = 140). Women using HCs exhibited significantly poorer extinction recall compared with naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists before fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories. Together, these findings suggest that HCs may impact women's ability to inhibit fear but that this impairment is not permanent and could potentially be alleviated with estrogen treatment. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Cholinergic blockade frees fear extinction from its contextual dependency

PubMed Central

Zelikowsky, Moriel; Hast, Timothy A.; Bennett, Rebecca Z.; Merjanian, Michael; Nocera, Nathaniel A.; Ponnusamy, Ravikumar; Fanselow, Michael S.

2012-01-01

Background Fears that are maladaptive or inappropriate can be reduced through extinction training. However, extinction is highly context-sensitive, resulting in the renewal of fear following shifts in context, and limiting the clinical efficacy of extinction training. Lesion and inactivation studies have shown that the contextualization of extinction depends on the hippocampus. Parallel studies have found that intrahippocampal scopolamine blocks contextual fear conditioning. Importantly, this effect was replicated using a non-invasive technique in which a low dose of scopolamine was administered systemically. We aimed to transfer the effects of this non-invasive approach to block the contextualization of fear extinction. Methods Rats were tone fear conditioned and extinguished under various systemic doses of scopolamine or the saline vehicle. They were subsequently tested (off drug) for tone fear in a context that was the same (controls) or shifted (renewal group) with respect to the extinction context. Results The lowest dose of scopolamine produced a significant attenuation of fear renewal when renewal was tested either in the original training context or a novel context. The drug also slowed the rate of long-term extinction memory formation, which was readily overcome by extending extinction training. Scopolamine only gave this effect when it was administered during, but not after extinction training. Higher doses of scopolamine severely disrupted extinction learning. Conclusions We discovered that disrupting contextual processing during extinction with the cholinergic antagonist scopolamine blocked subsequent fear renewal. Low doses of scopolamine may be a clinically promising adjunct to exposure therapy by making extinction more relapse-resistant. PMID:22981655

Baclofen facilitates the extinction of methamphetamine-induced conditioned place preference in rats

PubMed Central

Voigt, Robin M.; Herrold, Amy A.; Napier, T. Celeste

2011-01-01

The powerful, long-lasting association between the rewarding effects of a drug and contextual cues associated with drug administration can be studied using conditioned place preference (CPP). The GABAB receptor agonist baclofen facilitates the extinction of morphine-induced CPP in mice. The current study extended this work by determining if baclofen could enhance the extinction of methamphetamine (Meth) CPP. CPP was established using a six day conditioning protocol wherein Meth-pairings were alternated with saline-pairings. Rats were subsequently administered baclofen (2mg/kg i.p. or vehicle) immediately after each daily forced extinction session, which consisted of a saline injection immediately prior to being placed into the previously Meth- or saline-paired chamber. One extinction training cycle, consisted of six once-daily forced extinction sessions, mimicking the alternating procedure established during conditioning, followed by a test for preference (Ext test). CPP persisted for at least four extinction cycles in vehicle-treated rats. In contrast, CPP was inhibited following a single extinction training cycle. These data indicate that Meth-induced CPP was resistant to extinction, but extinction training was rendered effective when the training was combined with baclofen. These findings converge with the prior demonstration of baclofen facilitating the extinction of morphine-induced CPP indicating that GABAB receptor actions are independent of the primary (unconditioned) stimulus (i.e., the opiate or the stimulant) and likely reflect mechanisms engaged by extinction learning processes per se. Thus, baclofen administered in conjunction with extinction training may be of value for addiction therapy regardless of the class of drug being abused. PMID:21463025

Naloxone effects on extinction of ethanol- and cocaine-induced conditioned place preference in mice.

PubMed

Font, Laura; Houck, Christa A; Cunningham, Christopher L

2017-09-01

Previous studies found that naloxone (NLX) facilitated choice extinction of ethanol conditioned place preference (CPP) using long (60 min) test sessions, but there is little information on the variables determining this effect. These studies examined repeated exposure to NLX during extinction of ethanol- or cocaine-induced CPP using both short and long tests. DBA/2J mice were injected with NLX (0 or 10 mg/kg) before three 10- or 60-min choice extinction tests (experiment 1). All mice received a final 60-min test without NLX. Post-test NLX was given in experiment 2. Experiment 3 tested whether NLX would affect a forced extinction procedure. Experiment 4 tested its effect on extinction of cocaine-induced CPP. Pre-test (but not post-test) injections of NLX-facilitated choice extinction of ethanol CPP at both test durations. Pre-test NLX also facilitated forced extinction. However, pre-test NLX had no effect on choice extinction of cocaine CPP. Extinction test duration is not critical for engaging the opioid system during ethanol CPP extinction (experiment 1). Moreover, NLX's effect does not depend on CPP expression during extinction, just exposure to previously conditioned cues (experiment 3). The null effect of post-test NLX eliminates a memory consolidation interpretation (experiment 2) and the failure to alter cocaine CPP extinction argues against alteration of general learning or memory processes (experiment 4). Overall, these data suggest that the endogenous opioid system mediates a conditioned motivational effect that normally maintains alcohol-induced seeking behavior, which may underlie the efficacy of opiate antagonists in the treatment of alcoholism.

The effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy human sample.

PubMed

Acheson, Dean; Feifel, David; de Wilde, Sofieke; McKinney, Rebecca; Lohr, James; Risbrough, Victoria

2013-09-01

To improve outcomes for patients undergoing extinction-based therapies (e.g., exposure therapy) for anxiety disorders such as post-traumatic stress disorder (PTSD), there has been interest in identifying pharmaceutical compounds that might facilitate fear extinction learning and recall. Oxytocin (OT) is a mammalian neuropeptide that modulates activation of fear extinction-based neural circuits and fear responses. Little is known, however, about the effects of OT treatment on conditioned fear responding and extinction in humans. The purpose of the present study was to assess the effects of OT in a fear-potentiated startle task of fear conditioning and extinction. A double-blind, placebo-controlled study of 44 healthy human participants was conducted. Participants underwent a conditioned fear acquisition procedure, after which they were randomized to treatment group and delivered OT (24 IU) or placebo via intranasal (IN) spray. Forty-five minutes after treatment, participants underwent extinction training. Twenty-four hours later, subjects were tested for extinction recall. Relative to placebo, the OT group showed increased fear-potentiated startle responding during the earliest stage of extinction training relative to placebo; however, all treatment groups showed the same level of reduced responding by the end of extinction training. Twenty-four hours later, the OT group showed significantly higher recall of extinction relative to placebo. The current study provides preliminary evidence that OT may facilitate fear extinction recall in humans. These results support further study of OT as a potential adjunctive treatment for extinction-based therapies in fear-related disorders.

Neuroimaging of Fear-Associated Learning

PubMed Central

Greco, John A; Liberzon, Israel

2016-01-01

Fear conditioning has been commonly used as a model of emotional learning in animals and, with the introduction of functional neuroimaging techniques, has proven useful in establishing the neurocircuitry of emotional learning in humans. Studies of fear acquisition suggest that regions such as amygdala, insula, anterior cingulate cortex, and hippocampus play an important role in acquisition of fear, whereas studies of fear extinction suggest that the amygdala is also crucial for safety learning. Extinction retention testing points to the ventromedial prefrontal cortex as an essential region in the recall of the safety trace, and explicit learning of fear and safety associations recruits additional cortical and subcortical regions. Importantly, many of these findings have implications in our understanding of the pathophysiology of psychiatric disease. Recent studies using clinical populations have lent insight into the changes in regional activity in specific disorders, and treatment studies have shown how pharmaceutical and other therapeutic interventions modulate brain activation during emotional learning. Finally, research investigating individual differences in neurotransmitter receptor genotypes has highlighted the contribution of these systems in fear-associated learning. PMID:26294108

Affective-associative two-process theory: a neurocomputational account of partial reinforcement extinction effects.

PubMed

Lowe, Robert; Almér, Alexander; Billing, Erik; Sandamirskaya, Yulia; Balkenius, Christian

2017-12-01

The partial reinforcement extinction effect (PREE) is an experimentally established phenomenon: behavioural response to a given stimulus is more persistent when previously inconsistently rewarded than when consistently rewarded. This phenomenon is, however, controversial in animal/human learning theory. Contradictory findings exist regarding when the PREE occurs. One body of research has found a within-subjects PREE, while another has found a within-subjects reversed PREE (RPREE). These opposing findings constitute what is considered the most important problem of PREE for theoreticians to explain. Here, we provide a neurocomputational account of the PREE, which helps to reconcile these seemingly contradictory findings of within-subjects experimental conditions. The performance of our model demonstrates how omission expectancy, learned according to low probability reward, comes to control response choice following discontinuation of reward presentation (extinction). We find that a PREE will occur when multiple responses become controlled by omission expectation in extinction, but not when only one omission-mediated response is available. Our model exploits the affective states of reward acquisition and reward omission expectancy in order to differentially classify stimuli and differentially mediate response choice. We demonstrate that stimulus-response (retrospective) and stimulus-expectation-response (prospective) routes are required to provide a necessary and sufficient explanation of the PREE versus RPREE data and that Omission representation is key for explaining the nonlinear nature of extinction data.

Neural correlates of appetitive extinction in humans.

PubMed

Kruse, Onno; Tapia León, Isabell; Stark, Rudolf; Klucken, Tim

2017-01-01

Appetitive extinction receives attention as an important model for the treatment of psychiatric disorders. However, in humans, its underlying neural correlates remain unknown. To close this gap, we investigated appetitive acquisition and extinction with fMRI in a 2-day monetary incentive delay paradigm. During appetitive conditioning, one stimulus (CS+) was paired with monetary reward, while another stimulus (CS-) was never rewarded. Twenty-four hours later, subjects underwent extinction, in which neither CS was reinforced. Appetitive conditioning elicited stronger skin conductance responses to the CS+ as compared with the CS-. Regarding subjective ratings, the CS+ was rated more pleasant and arousing than the CS- after conditioning. Furthermore, fMRI-results (CS+ - CS-) showed activation of the reward circuitry including amygdala, midbrain and striatal areas. During extinction, conditioned responses were successfully extinguished. In the early phase of extinction, we found a significant activation of the caudate, the hippocampus, the dorsal and ventral anterior cingulate cortex (dACC and vACC). In the late phase, we found significant activation of the nucleus accumbens (NAcc) and the amygdala. Correlational analyses with subjective ratings linked extinction success to the vACC and the NAcc, while associating the dACC with reduced extinction. The results reveal neural correlates of appetitive extinction in humans and extend assumptions from models for human extinction learning. © The Author (2016). Published by Oxford University Press.

[Learning to solve a spatial task in a water maze in aggressive and submissive mice].

PubMed

Dubrovina, N I; Tomilenko, R A

2007-01-01

Learning and retention of the spatial memory were studied in mice with alternative under conditions of various experimental protocols. Visible and hidden platform acquisition in a simple model of the water maze was similarly fast both in aggressive and submissive mice, but extinction differed. Retention of the platform location preference persisted in aggressive mice in four testing trials. In submissive mice, extiction of the spatial memory was accompanied with a prolongation of search with parallel production of episodes of "passive drift". Differences in spatial learning between aggressive and submissive mice were revealed in a water maze complicated with partitions. In this case, aggressors were able to learn the position of a hidden platform (in contrast to submissive mice with the dominant response of "passive drift"). During testing the response, aggressive mice longer retained the spatial preference without extinction.

Extinction of alcohol seeking is enhanced by compound extinction and the noradrenaline reuptake inhibitor atomoxetine.

PubMed

Leung, Hiu T; Corbit, Laura H

2017-01-01

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli provides a means for reducing their impact on relapse. However, the expression of extinction can be disrupted by exposure to the previous reinforcer as well as the simple passage of time. We investigated whether augmentation of prediction error or of noradrenaline neurotransmission by the reuptake inhibitor atomoxetine would enhance long-term extinction of alcohol-seeking behavior. Rats received Pavlovian conditioning of multiple stimuli signaling the delivery of an alcohol reward before individual extinction was given to each of these stimuli. Further extinction was then given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg/kg; Experiment 2). Experiment 3 examined whether the compound stimulus effect relied on noradrenergic activity by testing the effects of the β-adrenergic antagonist propranolol, given prior to compound stimulus trials. Long-term retention of extinction learning was assessed a week later. Compound stimulus presentations enhanced long-term extinction as the stimulus extinguished in compound elicited less responding than a stimulus receiving equal extinction alone when tested a week later. This effect was mimicked by atomoxetine and blocked by propranolol given during extinction training. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Both behavioral and neurobiological processes could be exploited to enhance the outcome of extinction-based treatments for alcohol use disorders. © 2015 Society for the Study of Addiction.

The Melatonergic System in Anxiety Disorders and the Role of Melatonin in Conditional Fear.

PubMed

Huang, F; Yang, Z; Li, C-Q

2017-01-01

Resistance to extinction of certain conditioned responses forms the basis of anxieties, phobias, and compulsions. There has been an available effective means of extinction-based exposure psychotherapy for the treatment of anxiety disorders, such as posttraumatic stress disorder (PTSD) that has been hypothesized to result from impaired extinction of fear memory. PTSD is considered as a memory disorder within a Pavlovian fear conditioning and extinction framework. Therefore, the aim of this review was to report the preclinical profile of melatonin, a pineal gland hormone, as a potential pharmacological option in the treatment of anxiety disorders such as PTSD, tested with the Pavlovian fear conditioning paradigm. We performed a literature review regarding studies that evaluated the effects of melatonin on fear conditioning and fear extinction. Results showed that a single administration 30min before conditioning has no effect on the acquisition of cued fear, but impaired contextual fear conditioning. Compared to rats injected with vehicle, rats injected with melatonin 30min before extinction training presented a significant lower freezing during both extinction training and extinction test phases. However, melatonin injected immediately after extinction training was ineffective on extinction learning. Melatonin impaired contextual fear conditioning, a hippocampus-dependent task. On the contrary, melatonin facilitates the extinction of conditional cued fear without affecting its acquisition or expression, and melatonin facilitates cued fear extinction only when it is present during extinction training. Although further studies are necessary, the research undertaken until now shows that melatonin modulates fear conditioning and fear extinction and consequently melatonin may serve as an agent for the treatment of PTSD. © 2017 Elsevier Inc. All rights reserved.

Candesartan ameliorates impaired fear extinction induced by innate immune activation.

PubMed

Quiñones, María M; Maldonado, Lizette; Velazquez, Bethzaly; Porter, James T

2016-02-01

Patients with post-traumatic stress disorder (PTSD) tend to show signs of a relatively increased inflammatory state suggesting that activation of the immune system may contribute to the development of PTSD. In the present study, we tested whether activation of the innate immune system can disrupt acquisition or recall of auditory fear extinction using an animal model of PTSD. Male adolescent rats received auditory fear conditioning in context A. The next day, an intraperitoneal injection of lipopolysaccharide (LPS; 100 μg/kg) prior to auditory fear extinction in context B impaired acquisition and recall of extinction. LPS (100 μg/kg) given after extinction training did not impair extinction recall suggesting that LPS did not affect consolidation of extinction. In contrast to cued fear extinction, contextual fear extinction was not affected by prior injection of LPS (100 μg/kg). Although LPS also reduced locomotion, we could dissociate the effects of LPS on extinction and locomotion by using a lower dose of LPS (50 μg/kg) which impaired locomotion without affecting extinction. In addition, 15 h after an injection of 250 μg/kg LPS in adult rats, extinction learning and recall were impaired without affecting locomotion. A sub-chronic treatment with candesartan, an angiotensin II type 1 receptor blocker, prevented the LPS-induced impairment of extinction in adult rats. Our results demonstrate that activation of the innate immune system can disrupt auditory fear extinction in adolescent and adult animals. These findings also provide direction for clinical studies of novel treatments that modulate the innate immune system for stress-related disorders like PTSD. Copyright © 2015 Elsevier Inc. All rights reserved.

Hippocampal Erk Mechanisms Linking Prediction Error to Fear Extinction: Roles of Shock Expectancy and Contextual Aversive Valence

ERIC Educational Resources Information Center

Huh, Kyu Hwan; Guzman, Yomayra F.; Tronson, Natalie C.; Guedea, Anita L.; Gao, Can; Radulovic, Jelena

2009-01-01

Extinction of fear requires learning that anticipated aversive events no longer occur. Animal models reveal that sustained phosphorylation of the extracellular signal-regulated kinase (Erk) in hippocampal CA1 neurons plays an important role in this process. However, the key signals triggering and regulating the activity of Erk are not known. By…

Activation of the Infralimbic Cortex in a Fear Context Enhances Extinction Learning

ERIC Educational Resources Information Center

Thompson, Brittany M.; Baratta, Michael V.; Biedenkapp, Joseph C.; Rudy, Jerry W.; Watkins, Linda R.; Maier, Steven F.

2010-01-01

Activation of the infralimbic region (IL) of the medial prefrontal cortex (mPFC) reduces conditioned fear in a variety of situations, and the IL is thought to play an important role in the extinction of conditioned fear. Here we report a series of experiments using contextual fear conditioning in which the IL is activated with the GABAa antagonist…

Inactivation of the Anterior Cingulate Cortex Impairs Extinction of Rabbit Jaw Movement Conditioning and Prevents Extinction-Related Inhibition of Hippocampal Activity

ERIC Educational Resources Information Center

Griffin, Amy L.; Berry, Stephen D.

2004-01-01

Although past research has highlighted the involvement of limbic structures such as the anterior cingulate cortex (ACC) and hippocampus in learning, few have addressed the nature of their interaction. The current study of rabbit jaw movement conditioning used a combination of reversible lesions and electrophysiology to examine the involvement of…

Revisiting propranolol and PTSD: Memory erasure or extinction enhancement?

PubMed Central

Giustino, Thomas F.; Fitzgerald, Paul J.; Maren, Stephen

2016-01-01

Posttraumatic stress disorder (PTSD) has been described as the only neuropsychiatric disorder with a known cause, yet effective behavioral and pharmacotherapies remain elusive for many afflicted individuals. PTSD is characterized by heightened noradrenergic signaling, as well as a resistance to extinction learning. Research aimed at promoting more effective treatment of PTSD has focused on memory erasure (disrupting reconsolidation) and/or enhancing extinction retention through pharmacological manipulations. Propranolol, a β-adrenoceptor antagonist, has received considerable attention for its therapeutic potential in PTSD, although its impact on patients is not always effective. In this review, we briefly examine the consequences of β-noradrenergic manipulations on both reconsolidation and extinction learning in rodents and in humans. We suggest that propranolol is effective as a fear-reducing agent when paired with behavioral therapy soon after trauma when psychological stress is high, possibly preventing or dampening the later development of PTSD. In individuals who have already suffered from PTSD for a significant period of time, propranolol may be less effective at disrupting reconsolidation of strong fear memories. Also, when PTSD has already developed, chronic treatment with propranolol may be more effective than acute intervention, given that individuals with PTSD tend to experience long-term, elevated noradrenergic hyperarousal. PMID:26808441

Effect of ablated hippocampal neurogenesis on the formation and extinction of contextual fear memory

PubMed Central

Ko, Hyoung-Gon; Jang, Deok-Jin; Son, Junehee; Kwak, Chuljung; Choi, Jun-Hyeok; Ji, Young-Hoon; Lee, Yun-Sil; Son, Hyeon; Kaang, Bong-Kiun

2009-01-01

Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory. PMID:19138433

Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction.

PubMed

Kutlu, Munir Gunes; Cole, Robert D; Connor, David A; Natwora, Brendan; Gould, Thomas J

2018-03-01

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

Fear extinction deficits following acute stress associate with increased spine density and dendritic retraction in basolateral amygdala neurons.

PubMed

Maroun, Mouna; Ioannides, Pericles J; Bergman, Krista L; Kavushansky, Alexandra; Holmes, Andrew; Wellman, Cara L

2013-08-01

Stress-sensitive psychopathologies such as post-traumatic stress disorder are characterized by deficits in fear extinction and dysfunction of corticolimbic circuits mediating extinction. Chronic stress facilitates fear conditioning, impairs extinction, and produces dendritic proliferation in the basolateral amygdala (BLA), a critical site of plasticity for extinction. Acute stress impairs extinction, alters plasticity in the medial prefrontal cortex-to-BLA circuit, and causes dendritic retraction in the medial prefrontal cortex. Here, we examined extinction learning and basolateral amygdala pyramidal neuron morphology in adult male rats following a single elevated platform stress. Acute stress impaired extinction acquisition and memory, and produced dendritic retraction and increased mushroom spine density in basolateral amygdala neurons in the right hemisphere. Unexpectedly, irrespective of stress, rats that underwent fear and extinction testing showed basolateral amygdala dendritic retraction and altered spine density relative to non-conditioned rats, particularly in the left hemisphere. Thus, extinction deficits produced by acute stress are associated with increased spine density and dendritic retraction in basolateral amygdala pyramidal neurons. Furthermore, the finding that conditioning and extinction as such was sufficient to alter basolateral amygdala morphology and spine density illustrates the sensitivity of basolateral amygdala morphology to behavioral manipulation. These findings may have implications for elucidating the role of the amygdala in the pathophysiology of stress-related disorders. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

The extinction of morphine-induced conditioned place preference by histone deacetylase inhibition.

PubMed

Wang, Ru; Zhang, Yan; Qing, Hua; Liu, Mei; Yang, Peng

2010-10-11

Recent evidence suggests that epigenetic mechanisms have an important role in the development of addictive behavior. However, little is known about the role of epigenetic mechanisms in the extinction of morphine-induced behavioral changes. In this study, we will examine the effect of histone deacetylase (HDAC) inhibitors on extinction of morphine-induced conditioned place preference (CPP). To facilitate extinction, rats will be administered an HDAC inhibitor (HDACi) following nonreinforced exposure to the conditioned context. To measure persistence, rats were subject to a reinstatement test using 3 mg/kg dose of morphine. To exclude the effect of repeated NaBut injections themselves on morphine-CPP in the absence of extinction session, rats received injection of either NaBut or vehicle for 8 days. We found that HDAC inhibition during nonconfined extinction or confined extinction consolidation can facilitate extinction of morphine-induced CPP. We also showed that the extinction of drug seeking via HDAC inhibition modulates extinction learning such that reinstatement behavior is significantly attenuated. There is no effect of repeated NaBut injections themselves on morphine-CPP in the absence of extinction session. In conclusion, our results extend earlier reports on the ability of HDACi to modify the behavioral effects of drugs of abuse. Our increasing understanding of these epigenetic mechanisms will provide key answers to basic processes in drug addiction and hopefully provide insight into designing improved treatments for drug addiction. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Transitive inference in adults with autism spectrum disorders

PubMed Central

Solomon, Marjorie; Frank, Michael J.; Smith, Anne C.; Ly, Stanford; Carter, Cameron S.

2012-01-01

Individuals with autism spectrum disorders (ASDs) exhibit intact rote learning with impaired generalization. A transitive inference paradigm, involving training on four sequentially presented stimulus pairs containing overlapping items, with subsequent testing on two novel pairs, was used to investigate this pattern of learning in 27 young adults with ASDs and 31 matched neurotypical individuals (TYPs). On the basis of findings about memory and neuropathology, we hypothesized that individuals with ASDs would use a relational flexibility/conjunctive strategy reliant on an intact hippocampus, versus an associative strength/value transfer strategy requiring intact interactions between the prefrontal cortex and the striatum. Hypotheses were largely confirmed. ASDs demonstrated reduced interference from intervening pairs in early training; only TYPs formed a serial position curve by test; and ASDs exhibited impairments on the novel test pair consisting of end items with intact performance on the inner test pair. However, comparable serial position curves formed for both groups by the end of the first block. PMID:21656344

Intact implicit statistical learning in borderline personality disorder.

PubMed

Unoka, Zsolt; Vizin, Gabriella; Bjelik, Anna; Radics, Dóra; Nemeth, Dezso; Janacsek, Karolina

2017-09-01

Wide-spread neuropsychological deficits have been identified in borderline personality disorder (BPD). Previous research found impairments in decision making, declarative memory, working memory and executive functions; however, no studies have focused on implicit learning in BPD yet. The aim of our study was to investigate implicit statistical learning by comparing learning performance of 19 BPD patients and 19 healthy, age-, education- and gender-matched controls on a probabilistic sequence learning task. Moreover, we also tested whether participants retain the acquired knowledge after a delay period. To this end, participants were retested on a shorter version of the same task 24h after the learning phase. We found intact implicit statistical learning as well as retention of the acquired knowledge in this personality disorder. BPD patients seem to be able to extract and represent regularities implicitly, which is in line with the notion that implicit learning is less susceptible to illness compared to the more explicit processes. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model

PubMed Central

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-01-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction. PMID:27617747

Effects of a Context Shift and Multiple Context Extinction on Reactivity to Alcohol Cues

PubMed Central

MacKillop, James; Lisman, Stephen A.

2008-01-01

Cue exposure treatment (CET) attempts to reduce the influence of conditioned substance cues on addictive behavior via prolonged cue exposure with response prevention (i.e., extinction), but has received only modest empirical support in clinical trials. This may be because extinction learning appears to be context dependent and a change in context may result in a return of conditioned responding (i.e., renewal), although this has received only limited empirical examination. The current study used a four-session laboratory analogue of CET to examine whether a change in context following three sessions of alcohol cue exposure with response prevention would result in renewal of conditioned responding. In addition, this study examined whether conducting extinction in multiple contexts would attenuate renewal of conditioned responding. In a one-way between-subjects design, 73 heavy drinkers (71% male) were randomized to three conditions: 1) single context extinction (extinction to alcohol cues in the same context for three sessions followed by a context shift at the fourth session); 2) multiple context extinction (extinction to alcohol cues in different contexts each day for all four sessions); and 3) pseudo-extinction control condition (exposure to neutral cues in the same context for three sessions followed by exposure to alcohol cues at the fourth session). The results revealed the predicted cue reactivity and extinction effects, but the hypotheses that a context shift would generate renewed cue reactivity and that multiple contexts would enhance extinction were not supported. Methodological aspects of the study and the need for parametric data on the context dependency of extinction to alcohol cues are discussed. PMID:18729687

Uncertainty-Dependent Extinction of Fear Memory in an Amygdala-mPFC Neural Circuit Model.

PubMed

Li, Yuzhe; Nakae, Ken; Ishii, Shin; Naoki, Honda

2016-09-01

Uncertainty of fear conditioning is crucial for the acquisition and extinction of fear memory. Fear memory acquired through partial pairings of a conditioned stimulus (CS) and an unconditioned stimulus (US) is more resistant to extinction than that acquired through full pairings; this effect is known as the partial reinforcement extinction effect (PREE). Although the PREE has been explained by psychological theories, the neural mechanisms underlying the PREE remain largely unclear. Here, we developed a neural circuit model based on three distinct types of neurons (fear, persistent and extinction neurons) in the amygdala and medial prefrontal cortex (mPFC). In the model, the fear, persistent and extinction neurons encode predictions of net severity, of unconditioned stimulus (US) intensity, and of net safety, respectively. Our simulation successfully reproduces the PREE. We revealed that unpredictability of the US during extinction was represented by the combined responses of the three types of neurons, which are critical for the PREE. In addition, we extended the model to include amygdala subregions and the mPFC to address a recent finding that the ventral mPFC (vmPFC) is required for consolidating extinction memory but not for memory retrieval. Furthermore, model simulations led us to propose a novel procedure to enhance extinction learning through re-conditioning with a stronger US; strengthened fear memory up-regulates the extinction neuron, which, in turn, further inhibits the fear neuron during re-extinction. Thus, our models increased the understanding of the functional roles of the amygdala and vmPFC in the processing of uncertainty in fear conditioning and extinction.

Genetic component in learning ability in bees.

PubMed

Kerr, W E; Moura Duarte, F A; Oliveira, R S

1975-10-01

Twenty-five bees, five from each of five hives, were trained to collect food at a table. When the bee reached the table, time was recorded for 12 visits. Then a blue and yellow pan was substituted for the original metal pan, and time and correct responses were recorded for 30 trips (discrimination phase). Finally, food was taken from the pan and extinction was recorded as incorrect responses for 20 visits. Variance analysis was carried out, and genetic variance was undetected for discrimination, but was detected for extinction. It is concluded that learning is very important for bees, so that any impairment in such ability affects colony survival.

Infralimbic GluN2A-Containing NMDA Receptors Modulate Reconsolidation of Cocaine Self-Administration Memory.

PubMed

Hafenbreidel, Madalyn; Rafa Todd, Carolynn; Mueller, Devin

2017-04-01

Addiction is characterized by high relapse susceptibility, and relapse can be triggered by drug-associated cues. Cue presentation induces retrieval of the drug-cue memory, which becomes labile and must be reconsolidated into long-term storage. Repeated unpaired cue presentation, however, promotes extinction. Cue-reactivity can be reduced by blocking reconsolidation or facilitating extinction, which are mediated by NMDA receptors (NMDArs). However, the role of NMDArs in either process following self-administration is unclear. Thus, to determine their role in extinction, rats learned to self-administer cocaine before receiving injections of the NMDAr antagonist CPP immediately after four 45-min extinction sessions. During a subsequent 90-min extinction retention test, CPP-treated rats lever pressed less than saline-treated rats indicating that NMDAr blockade facilitated extinction or disrupted drug-cue memory reconsolidation. In addition, infusing CPP into the infralimbic medial prefrontal cortex (IL-mPFC), a structure implicated in extinction, before four 45-min or immediately after four 30min extinction sessions, had similar results during the extinction retention tests. Next, the GluN2A-selective antagonist NVP or GluN2B-selective antagonist Ro25 was infused into IL-mPFC or nucleus accumbens (NAc) shell, another structure implicated in extinction, after four 45-min extinction sessions. Blocking GluN2A-, but not GluN2B-, containing NMDArs, in IL-mPFC or NAc shell reduced lever pressing during the extinction retention tests. Finally, to dissociate reconsolidation from extinction, NVP was infused into IL-mPFC after four 10-min reactivation sessions, which resulted in reduced lever pressing during the retention test. These results indicate that IL-mPFC GluN2A-containing NMDArs modulate reconsolidation, and suggest a novel treatment strategy, as reducing cue reactivity could limit relapse susceptibility.

Involvement of BDNF signaling transmission from basolateral amygdala to infralimbic prefrontal cortex in conditioned taste aversion extinction.

PubMed

Xin, Jian; Ma, Ling; Zhang, Tian-Yi; Yu, Hui; Wang, Yue; Kong, Liang; Chen, Zhe-Yu

2014-05-21

Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase receptor B (TrkB), play a critical role in memory extinction. However, the detailed role of BDNF in memory extinction on the basis of neural circuit has not been fully understood. Here, we aim to investigate the role of BDNF signaling circuit in mediating conditioned taste aversion (CTA) memory extinction of the rats. We found region-specific changes in BDNF gene expression during CTA extinction. CTA extinction led to increased BDNF gene expression in the basolateral amygdala (BLA) and infralimbic prefrontal cortex (IL) but not in the central amygdaloid nucleus (CeA) and hippocampus (HIP). Moreover, blocking BDNF signaling or exogenous microinjection of BDNF into the BLA or IL could disrupt or enhance CTA extinction, which suggested that BDNF signaling in the BLA and IL is necessary and sufficient for CTA extinction. Interestingly, we found that microinjection of BDNF-neutralizing antibody into the BLA could abolish the extinction training-induced BDNF mRNA level increase in the IL, but not vice versa, demonstrating that BDNF signaling is transmitted from the BLA to IL during extinction. Finally, the accelerated extinction learning by infusion of exogenous BDNF in the BLA could also be blocked by IL infusion of BDNF-neutralizing antibody rather than vice versa, indicating that the IL, but not BLA, is the primary action site of BDNF in CTA extinction. Together, these data suggest that BLA-IL circuit regulates CTA memory extinction by identifying BDNF as a key regulator. Copyright © 2014 the authors 0270-6474/14/347302-12$15.00/0.

Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches

PubMed Central

Maurer, Verena; Murphy, Conor; Schmuckermair, Claudia; Muigg, Patrick; Neumann, Inga D.; Whittle, Nigel

2016-01-01

Background: Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear. Methods: The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse. Results: Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice. Conclusions: By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term. PMID:26625894

Combined Neuropeptide S and D-Cycloserine Augmentation Prevents the Return of Fear in Extinction-Impaired Rodents: Advantage of Dual versus Single Drug Approaches.

PubMed

Sartori, Simone B; Maurer, Verena; Murphy, Conor; Schmuckermair, Claudia; Muigg, Patrick; Neumann, Inga D; Whittle, Nigel; Singewald, Nicolas

2016-06-01

Despite its success in treating specific anxiety disorders, the effect of exposure therapy is limited by problems with tolerability, treatment resistance, and fear relapse after initial response. The identification of novel drug targets facilitating fear extinction in clinically relevant animal models may guide improved treatment strategies for these disorders in terms of efficacy, acceleration of fear extinction, and return of fear. The extinction-facilitating potential of neuropeptide S, D-cycloserine, and a benzodiazepine was investigated in extinction-impaired high anxiety HAB rats and 129S1/SvImJ mice using a classical cued fear conditioning paradigm followed by extinction training and several extinction test sessions to study fear relapse. Administration of D-cycloserine improved fear extinction in extinction-limited, but not in extinction-deficient, rodents compared with controls. Preextinction neuropeptide S caused attenuated fear responses in extinction-deficient 129S1/SvImJ mice at extinction training onset and further reduced freezing during this session. While the positive effects of either D-cycloserine or neuropeptide S were not persistent in 129S1/SvImJ mice after 10 days, the combination of preextinction neuropeptide S with postextinction D-cycloserine rendered the extinction memory persistent and context independent up to 5 weeks after extinction training. This dual pharmacological adjunct to extinction learning also protected against fear reinstatement in 129S1/SvImJ mice. By using the potentially nonsedative anxiolytic neuropeptide S and the cognitive enhancer D-cycloserine to facilitate deficient fear extinction, we provide here the first evidence of a purported efficacy of a dual over a single drug approach. This approach may render exposure sessions less aversive and more efficacious for patients, leading to enhanced protection from fear relapse in the long term. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Drivers of extinction risk in African mammals: the interplay of distribution state, human pressure, conservation response and species biology

PubMed Central

Di Marco, Moreno; Buchanan, Graeme M.; Szantoi, Zoltan; Holmgren, Milena; Grottolo Marasini, Gabriele; Gross, Dorit; Tranquilli, Sandra; Boitani, Luigi; Rondinini, Carlo

2014-01-01

Although conservation intervention has reversed the decline of some species, our success is outweighed by a much larger number of species moving towards extinction. Extinction risk modelling can identify correlates of risk and species not yet recognized to be threatened. Here, we use machine learning models to identify correlates of extinction risk in African terrestrial mammals using a set of variables belonging to four classes: species distribution state, human pressures, conservation response and species biology. We derived information on distribution state and human pressure from satellite-borne imagery. Variables in all four classes were identified as important predictors of extinction risk, and interactions were observed among variables in different classes (e.g. level of protection, human threats, species distribution ranges). Species biology had a key role in mediating the effect of external variables. The model was 90% accurate in classifying extinction risk status of species, but in a few cases the observed and modelled extinction risk mismatched. Species in this condition might suffer from an incorrect classification of extinction risk (hence require reassessment). An increased availability of satellite imagery combined with improved resolution and classification accuracy of the resulting maps will play a progressively greater role in conservation monitoring. PMID:24733953

Drivers of extinction risk in African mammals: the interplay of distribution state, human pressure, conservation response and species biology.

PubMed

Di Marco, Moreno; Buchanan, Graeme M; Szantoi, Zoltan; Holmgren, Milena; Grottolo Marasini, Gabriele; Gross, Dorit; Tranquilli, Sandra; Boitani, Luigi; Rondinini, Carlo

2014-01-01

Although conservation intervention has reversed the decline of some species, our success is outweighed by a much larger number of species moving towards extinction. Extinction risk modelling can identify correlates of risk and species not yet recognized to be threatened. Here, we use machine learning models to identify correlates of extinction risk in African terrestrial mammals using a set of variables belonging to four classes: species distribution state, human pressures, conservation response and species biology. We derived information on distribution state and human pressure from satellite-borne imagery. Variables in all four classes were identified as important predictors of extinction risk, and interactions were observed among variables in different classes (e.g. level of protection, human threats, species distribution ranges). Species biology had a key role in mediating the effect of external variables. The model was 90% accurate in classifying extinction risk status of species, but in a few cases the observed and modelled extinction risk mismatched. Species in this condition might suffer from an incorrect classification of extinction risk (hence require reassessment). An increased availability of satellite imagery combined with improved resolution and classification accuracy of the resulting maps will play a progressively greater role in conservation monitoring.

The hypocretin/orexin system mediates the extinction of fear memories.

PubMed

Flores, África; Valls-Comamala, Victòria; Costa, Giulia; Saravia, Rocío; Maldonado, Rafael; Berrendero, Fernando

2014-11-01

Anxiety disorders are often associated with an inability to extinguish learned fear responses. The hypocretin/orexin system is involved in the regulation of emotional states and could also participate in the consolidation and extinction of aversive memories. Using hypocretin receptor-1 and hypocretin receptor-2 antagonists, hypocretin-1 and hypocretin-2 peptides, and hypocretin receptor-1 knockout mice, we investigated the role of the hypocretin system in cue- and context-dependent fear conditioning and extinction. Hypocretins were crucial for the consolidation of fear conditioning, and this effect was mainly observed in memories with a high emotional component. Notably, after the acquisition of fear memory, hypocretin receptor-1 blockade facilitated fear extinction, whereas hypocretin-1 administration impaired this extinction process. The extinction-facilitating effects of the hypocretin receptor-1 antagonist SB334867 were associated with increased expression of cFos in the basolateral amygdala and the infralimbic cortex. Intra-amygdala, but neither intra-infralimbic prefrontal cortex nor intra-dorsohippocampal infusion of SB334867 enhanced fear extinction. These results reveal a key role for hypocretins in the extinction of aversive memories and suggest that hypocretin receptor-1 blockade could represent a novel therapeutic target for the treatment of diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder and phobias.

Is aversive learning a marker of risk for anxiety disorders in children?

PubMed Central

Craske, Michelle G.; Waters, Allison M.; Bergman, R. Lindsey; Naliboff, Bruce; Lipp, Ottmar V.; Negoro, Hideki; Ornitz, Edward M.

2016-01-01

Aversive conditioning and extinction were evaluated in children with anxiety disorders (n = 23), at-risk for anxiety disorders (n = 15), and controls (n = 11). Participants underwent 16 trials of discriminative conditioning of two geometric figures, with (CS+) or without (CS−) an aversive tone (US), followed by 8 extinction trials (4 CS+, 4 CS−), and 8 extinction re-test trials averaging 2 weeks later. Skin conductance responses and verbal ratings of valence and arousal to the CS+/CS− stimuli were measured. Anxiety disordered children showed larger anticipatory and unconditional skin conductance responses across conditioning, and larger orienting and anticipatory skin conductance responses across extinction and extinction re-test, all to the CS+ and CS−, relative to controls. At-risk children showed larger unconditional responses during conditioning, larger orienting responses during the first block of extinction, and larger anticipatory responses during extinction re-test, all to the CS+ and CS−, relative to controls. Also, anxiety disordered children rated the CS+ as more unpleasant than the other groups. Elevated skin conductance responses to signals of threat (CS+) and signals of safety (CS−; CS+ during extinction) are discussed as features of manifestation of and risk for anxiety in children, compared to the specificity of valence judgments to the manifestation of anxiety. PMID:18539262

The Hypocretin/Orexin System Mediates the Extinction of Fear Memories

PubMed Central

Flores, África; Valls-Comamala, Victòria; Costa, Giulia; Saravia, Rocío; Maldonado, Rafael; Berrendero, Fernando

2014-01-01

Anxiety disorders are often associated with an inability to extinguish learned fear responses. The hypocretin/orexin system is involved in the regulation of emotional states and could also participate in the consolidation and extinction of aversive memories. Using hypocretin receptor-1 and hypocretin receptor-2 antagonists, hypocretin-1 and hypocretin-2 peptides, and hypocretin receptor-1 knockout mice, we investigated the role of the hypocretin system in cue- and context-dependent fear conditioning and extinction. Hypocretins were crucial for the consolidation of fear conditioning, and this effect was mainly observed in memories with a high emotional component. Notably, after the acquisition of fear memory, hypocretin receptor-1 blockade facilitated fear extinction, whereas hypocretin-1 administration impaired this extinction process. The extinction-facilitating effects of the hypocretin receptor-1 antagonist SB334867 were associated with increased expression of cFos in the basolateral amygdala and the infralimbic cortex. Intra-amygdala, but neither intra-infralimbic prefrontal cortex nor intra-dorsohippocampal infusion of SB334867 enhanced fear extinction. These results reveal a key role for hypocretins in the extinction of aversive memories and suggest that hypocretin receptor-1 blockade could represent a novel therapeutic target for the treatment of diseases associated with inappropriate retention of fear, such as post-traumatic stress disorder and phobias. PMID:24930888

Exposure to a Fearful Context during Periods of Memory Plasticity Impairs Extinction via Hyperactivation of Frontal-Amygdalar Circuits

ERIC Educational Resources Information Center

Stafford, James M.; Maughan, DeeAnna K.; Ilioi, Elena C.; Lattal, K. Matthew

2013-01-01

An issue of increasing theoretical and translational importance is to understand the conditions under which learned fear can be suppressed, or even eliminated. Basic research has pointed to extinction, in which an organism is exposed to a fearful stimulus (such as a context) in the absence of an expected aversive outcome (such as a shock). This…

A Field-Based Biomimicry Exercise Helps Students Discover Connections among Biodiversity, Form and Function, and Species Conservation during Earth's Sixth Extinction

ERIC Educational Resources Information Center

Soja, Constance M.

2014-01-01

In a first-year seminar on mass extinctions, a field-based, paleontology-focused exercise promotes active learning about Earth's biodiversity, form and function, and the biomimicry potential of ancient and modern life. Students study Devonian fossils at a local quarry and gain foundational experience in describing anatomy and relating form to…

Stimulus fear relevance and the speed, magnitude, and robustness of vicariously learned fear.

PubMed

Dunne, Güler; Reynolds, Gemma; Askew, Chris

2017-08-01

Superior learning for fear-relevant stimuli is typically indicated in the laboratory by faster acquisition of fear responses, greater learned fear, and enhanced resistance to extinction. Three experiments investigated the speed, magnitude, and robustness of UK children's (6-10 years; N = 290; 122 boys, 168 girls) vicariously learned fear responses for three types of stimuli. In two experiments, children were presented with pictures of novel animals (Australian marsupials) and flowers (fear-irrelevant stimuli) alone (control) or together with faces expressing fear or happiness. To determine learning speed the number of stimulus-face pairings seen by children was varied (1, 10, or 30 trials). Robustness of learning was examined via repeated extinction procedures over 3 weeks. A third experiment compared the magnitude and robustness of vicarious fear learning for snakes and marsupials. Significant increases in fear responses were found for snakes, marsupials and flowers. There was no indication that vicarious learning for marsupials was faster than for flowers. Moreover, vicariously learned fear was neither greater nor more robust for snakes compared to marsupials, or for marsupials compared to flowers. These findings suggest that for this age group stimulus fear relevance may have little influence on vicarious fear learning. Copyright © 2017 Elsevier Ltd. All rights reserved.

Prototype learning and dissociable categorization systems in Alzheimer's disease.

PubMed

Heindel, William C; Festa, Elena K; Ott, Brian R; Landy, Kelly M; Salmon, David P

2013-08-01

Recent neuroimaging studies suggest that prototype learning may be mediated by at least two dissociable memory systems depending on the mode of acquisition, with A/Not-A prototype learning dependent upon a perceptual representation system located within posterior visual cortex and A/B prototype learning dependent upon a declarative memory system associated with medial temporal and frontal regions. The degree to which patients with Alzheimer's disease (AD) can acquire new categorical information may therefore critically depend upon the mode of acquisition. The present study examined A/Not-A and A/B prototype learning in AD patients using procedures that allowed direct comparison of learning across tasks. Despite impaired explicit recall of category features in all tasks, patients showed differential patterns of category acquisition across tasks. First, AD patients demonstrated impaired prototype induction along with intact exemplar classification under incidental A/Not-A conditions, suggesting that the loss of functional connectivity within visual cortical areas disrupted the integration processes supporting prototype induction within the perceptual representation system. Second, AD patients demonstrated intact prototype induction but impaired exemplar classification during A/B learning under observational conditions, suggesting that this form of prototype learning is dependent on a declarative memory system that is disrupted in AD. Third, the surprisingly intact classification of both prototypes and exemplars during A/B learning under trial-and-error feedback conditions suggests that AD patients shifted control from their deficient declarative memory system to a feedback-dependent procedural memory system when training conditions allowed. Taken together, these findings serve to not only increase our understanding of category learning in AD, but to also provide new insights into the ways in which different memory systems interact to support the acquisition of categorical knowledge. Copyright © 2013 Elsevier Ltd. All rights reserved.

Prototype Learning and Dissociable Categorization Systems in Alzheimer’s Disease

PubMed Central

Heindel, William C.; Festa, Elena K.; Ott, Brian R.; Landy, Kelly M.; Salmon, David P.

2015-01-01

Recent neuroimaging studies suggest that prototype learning may be mediated by at least two dissociable memory systems depending on the mode of acquisition, with A/Not-A prototype learning dependent upon a perceptual representation system located within posterior visual cortex and A/B prototype learning dependent upon a declarative memory system associated with medial temporal and frontal regions. The degree to which patients with Alzheimer’s disease (AD) can acquire new categorical information may therefore critically depend upon the mode of acquisition. The present study examined A/Not-A and A/B prototype learning in AD patients using procedures that allowed direct comparison of learning across tasks. Despite impaired explicit recall of category features in all tasks, patients showed differential patterns of category acquisition across tasks. First, AD patients demonstrated impaired prototype induction along with intact exemplar classification under incidental A/Not-A conditions, suggesting that the loss of functional connectivity within visual cortical areas disrupted the integration processes supporting prototype induction within the perceptual representation system. Second, AD patients demonstrated intact prototype induction but impaired exemplar classification during A/B learning under observational conditions, suggesting that this form of prototype learning is dependent on a declarative memory system that is disrupted in AD. Third, the surprisingly intact classification of both prototypes and exemplars during A/B learning under trial-and-error feedback conditions suggests that AD patients shifted control from their deficient declarative memory system to a feedback-dependent procedural memory system when training conditions allowed. Taken together, these findings serve to not only increase our understanding of category learning in AD, but to also provide new insights into the ways in which different memory systems interact to support the acquisition of categorical knowledge. PMID:23751172

Fear extinction in the human brain: A meta-analysis of fMRI studies in healthy participants.

PubMed

Fullana, Miquel A; Albajes-Eizagirre, Anton; Soriano-Mas, Carles; Vervliet, Bram; Cardoner, Narcís; Benet, Olívia; Radua, Joaquim; Harrison, Ben J

2018-05-01

The study of fear extinction represents an important example of translational neuroscience in psychiatry and promises to improve the understanding and treatment of anxiety and fear-related disorders. We present the results of a set of meta-analyses of human fear extinction studies in healthy participants, conducted with functional magnetic resonance imaging (fMRI) and reporting whole-brain results. Meta-analyses of fear extinction learning primarily implicate consistent activation of brain regions linked to threat appraisal and experience, including the dorsal anterior cingulate and anterior insular cortices. An overlapping anatomical result was obtained from the meta-analysis of extinction recall studies, except when studies directly compared an extinguished threat stimulus to an unextinguished threat stimulus (instead of a safety stimulus). In this latter instance, more consistent activation was observed in dorsolateral and ventromedial prefrontal cortex regions, together with other areas including the hippocampus. While our results partially support the notion of a shared neuroanatomy between human and rodent models of extinction processes, they also encourage an expanded account of the neural basis of human fear extinction. Copyright © 2018 Elsevier Ltd. All rights reserved.

Brain structural connectivity and context-dependent extinction memory.

PubMed

Hermann, Andrea; Stark, Rudolf; Blecker, Carlo R; Milad, Mohammed R; Merz, Christian J

2017-08-01

Extinction of conditioned fear represents an important mechanism in the treatment of anxiety disorders. Return of fear after successful extinction or exposure therapy in patients with anxiety disorders might be linked to poor temporal or contextual generalization of extinction due to individual differences in brain structural connectivity. The goal of this magnetic resonance imaging study was therefore to investigate the association of context-dependent extinction recall with brain structural connectivity. Diffusion-tensor imaging was used to determine the fractional anisotropy as a measure of white matter structural integrity of fiber tracts connecting central brain regions of the fear and extinction circuit (uncinate fasciculus, cingulum). Forty-five healthy men participated in a two-day fear conditioning experiment with fear acquisition in context A and extinction learning in context B on the first day. Extinction recall in the extinction context as well as renewal in the acquisition context and a novel context C took place one day later. Renewal of conditioned fear (skin conductance responses) in the acquisition context was associated with higher structural integrity of the hippocampal part of the cingulum. Enhanced structural integrity of the cingulum might be related to stronger hippocampal modulation of the dorsal anterior cingulate cortex, a region important for modulating conditioned fear output by excitatory projections to the amygdala. This finding underpins the crucial role of individual differences in the structural integrity of relevant fiber tracts for context-dependent extinction recall and return of fear after exposure therapy in anxiety disorders. © 2017 Wiley Periodicals, Inc.

Cortisol disrupts the neural correlates of extinction recall.

PubMed

Kinner, Valerie L; Merz, Christian J; Lissek, Silke; Wolf, Oliver T

2016-06-01

The renewal effect describes the recovery of extinguished responses that may occur after a change in context and indicates that extinction memory retrieval is sometimes prone to failure. Stress hormones have been implicated to modulate extinction processes, with mostly impairing effects on extinction retrieval. However, the neurobiological mechanisms mediating stress effects on extinction memory remain elusive. In this functional magnetic resonance imaging study, we investigated the effects of cortisol administration on the neural correlates of extinction memory retrieval in a predictive learning task. In this task, participants were required to predict whether certain food stimuli were associated with stomach trouble when presented in two different contexts. A two-day renewal paradigm was applied in which an association was acquired in context A and subsequently extinguished in context B. On the following day, participants received either cortisol or placebo 40min before extinction memory retrieval was tested in both contexts. Behaviorally, cortisol impaired the retrieval of extinguished associations when presented in the extinction context. On the neural level, this effect was characterized by a reduced context differentiation for the extinguished stimulus in the ventromedial prefrontal cortex, but only in men. In the placebo group, ventromedial prefrontal cortex was functionally connected to the left cerebellum, the anterior cingulate and the right anterior parahippocampal gyrus to express extinction memory. This functional crosstalk was reduced under cortisol. These findings illustrate that the stress hormone cortisol disrupts ventromedial prefrontal cortex functioning and its communication with other brain regions implicated in extinction memory. Copyright © 2016 Elsevier Inc. All rights reserved.

Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.

PubMed

Micale, Vincenzo; Stepan, Jens; Jurik, Angela; Pamplona, Fabricio A; Marsch, Rudolph; Drago, Filippo; Eder, Matthias; Wotjak, Carsten T

2017-07-01

The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1. Copyright © 2017 Elsevier Ltd. All rights reserved.

Implicit Learning Deficits among Adults with Developmental Dyslexia

ERIC Educational Resources Information Center

Kahta, Shani; Schiff, Rachel

2016-01-01

The aim of the present study was to investigate implicit learning processes among adults with developmental dyslexia (DD) using a visual linguistic artificial grammar learning (AGL) task. Specifically, it was designed to explore whether the intact learning reported in previous studies would also occur under conditions including minimal training…

[Interaction of immobilization stress and food-getting learning].

PubMed

Levshina, I P; Stashkevich, I S; Shuĭkin, N N

2009-01-01

The behavioral effects of emotional negative stress (immobilization) were studied in Wistar rats intact and those that had previous positive emotion experience. The food-getting learning has been chosen as positive emotion experience. Animals were trained in food pellet-reaching task by their preferred paw. It was shown that immobilization of intact rats leads to suppression of motor activity and increasing the duration of grooming. These effects indicate enhancement of passive-avoidance reactions. It was also shown that motor learning in group of rats with food reinforcement before immobilisation significantly reduces appearance of passive-avoidance reactions. It was found that immobilization stress does not inverse the initial direction of limb preference in majority of rats.

Murine GRPR and Stathmin Control in Opposite Directions both Cued Fear Extinction and Neural Activities of the Amygdala and Prefrontal Cortex

PubMed Central

Martel, Guillaume; Hevi, Charles; Wong, Alexandra; Zushida, Ko; Uchida, Shusaku; Shumyatsky, Gleb P.

2012-01-01

Extinction is an integral part of normal healthy fear responses, while it is compromised in several fear-related mental conditions in humans, such as post-traumatic stress disorder (PTSD). Although much research has recently been focused on fear extinction, its molecular and cellular underpinnings are still unclear. The development of animal models for extinction will greatly enhance our approaches to studying its neural circuits and the mechanisms involved. Here, we describe two gene-knockout mouse lines, one with impaired and another with enhanced extinction of learned fear. These mutant mice are based on fear memory-related genes, stathmin and gastrin-releasing peptide receptor (GRPR). Remarkably, both mutant lines showed changes in fear extinction to the cue but not to the context. We performed indirect imaging of neuronal activity on the second day of cued extinction, using immediate-early gene c-Fos. GRPR knockout mice extinguished slower (impaired extinction) than wildtype mice, which was accompanied by an increase in c-Fos activity in the basolateral amygdala and a decrease in the prefrontal cortex. By contrast, stathmin knockout mice extinguished faster (enhanced extinction) and showed a decrease in c-Fos activity in the basolateral amygdala and an increase in the prefrontal cortex. At the same time, c-Fos activity in the dentate gyrus was increased in both mutant lines. These experiments provide genetic evidence that the balance between neuronal activities of the amygdala and prefrontal cortex defines an impairment or facilitation of extinction to the cue while the hippocampus is involved in the context-specificity of extinction. PMID:22312434

Murine GRPR and stathmin control in opposite directions both cued fear extinction and neural activities of the amygdala and prefrontal cortex.

PubMed

Martel, Guillaume; Hevi, Charles; Wong, Alexandra; Zushida, Ko; Uchida, Shusaku; Shumyatsky, Gleb P

2012-01-01

Extinction is an integral part of normal healthy fear responses, while it is compromised in several fear-related mental conditions in humans, such as post-traumatic stress disorder (PTSD). Although much research has recently been focused on fear extinction, its molecular and cellular underpinnings are still unclear. The development of animal models for extinction will greatly enhance our approaches to studying its neural circuits and the mechanisms involved. Here, we describe two gene-knockout mouse lines, one with impaired and another with enhanced extinction of learned fear. These mutant mice are based on fear memory-related genes, stathmin and gastrin-releasing peptide receptor (GRPR). Remarkably, both mutant lines showed changes in fear extinction to the cue but not to the context. We performed indirect imaging of neuronal activity on the second day of cued extinction, using immediate-early gene c-Fos. GRPR knockout mice extinguished slower (impaired extinction) than wildtype mice, which was accompanied by an increase in c-Fos activity in the basolateral amygdala and a decrease in the prefrontal cortex. By contrast, stathmin knockout mice extinguished faster (enhanced extinction) and showed a decrease in c-Fos activity in the basolateral amygdala and an increase in the prefrontal cortex. At the same time, c-Fos activity in the dentate gyrus was increased in both mutant lines. These experiments provide genetic evidence that the balance between neuronal activities of the amygdala and prefrontal cortex defines an impairment or facilitation of extinction to the cue while the hippocampus is involved in the context-specificity of extinction.

Learning and memory performance in breast cancer survivors 2 to 6 years post-treatment: the role of encoding versus forgetting.

PubMed

Root, James C; Andreotti, Charissa; Tsu, Loretta; Ellmore, Timothy M; Ahles, Tim A

2016-06-01

Our previous retrospective analysis of clinically referred breast cancer survivors' performance on learning and memory measures found a primary weakness in initial encoding of information into working memory with intact retention and recall of this same information at a delay. This suggests that survivors may misinterpret cognitive lapses as being due to forgetting when, in actuality, they were not able to properly encode this information at the time of initial exposure. Our objective in this study was to replicate and extend this pattern of performance to a research sample to increase the generalizability of this finding in a sample in which subjects were not clinically referred for cognitive issues. We contrasted learning and memory performance between breast cancer survivors on endocrine therapy 2 to 6 years post-treatment with age- and education-matched healthy controls. We then stratified lower- and higher-performing breast cancer survivors to examine specific patterns of learning and memory performance. Contrasts were generated for four aggregate visual and verbal memory variables from the California Verbal Learning Test-2 (CVLT-2) and the Brown Location Test (BLT): Single-trial Learning: Trial 1 performance, Multiple-trial Learning: Trial 5 performance, Delayed Recall: Long-delay Recall performance, and Memory Errors: False-positive errors. As predicted, breast cancer survivors' performance as a whole was significantly lower on Single-trial Learning than the healthy control group but exhibited no significant difference in Delayed Recall. In the secondary analysis contrasting lower- and higher-performing survivors on cognitive measures, the same pattern of lower Single-trial Learning performance was exhibited in both groups, with the additional finding of significantly weaker Multiple-trial Learning performance in the lower-performing breast cancer group and intact Delayed Recall performance in both groups. As with our earlier finding of weaker initial encoding with intact recall in a cohort of clinically referred breast cancer survivors, our results indicate this same profile in a research sample of breast cancer survivors. Further, when the breast cancer group was stratified by lower and higher performance, both groups exhibited significantly lower performance on initial encoding, with more pronounced encoding weakness in the lower-performing group. As in our previous research, survivors did not lose successfully encoded information over longer delays, either in the lower- or higher-performing group, again arguing against memory decay in survivors. The finding of weaker initial encoding of information together with intact delayed recall in survivors points to specific treatment interventions in rehabilitation of cognitive dysfunction. The finding of weaker initial encoding of information together with intact delayed recall in survivors points to specific treatment interventions in rehabilitation of cognitive dysfunction and is discussed.

Easy to remember, difficult to forget: the development of fear regulation

PubMed Central

Johnson, D.C.; Casey, B.J.

2014-01-01

Fear extinction learning is a highly adaptive process that involves the integrity of frontolimbic circuitry. Its disruption has been associated with emotional dysregulation in stress and anxiety disorders. In this article we consider how age, genetics and experiences shape our capacity to regulate fear in cross-species studies. Evidence for adolescent-specific diminished fear extinction learning is presented in the context of immature frontolimbic circuitry. We also present evidence for less neural plasticity in fear regulation as a function of early life stress and by genotype, focusing on the common brain derived neurotrophin factor (BDNF) Val66Met polymorphism. Finally, we discuss this work in the context of exposure-based behavioral therapies for the treatment of anxiety and stress disorders that are based on principles of fear extinction. We conclude by speculating on how such therapies may be optimized for the individual based on the patient’s age, genetic profile and personal history to move from standard treatment of care to personalized and precision medicine. PMID:25238998

Positive affect protects against deficient safety learning during extinction of fear of movement-related pain in healthy individuals scoring relatively high on trait anxiety.

PubMed

Meulders, Ann; Meulders, Michel; Vlaeyen, Johan W S

2014-06-01

From a treatment perspective, it is highly relevant to pinpoint individual vulnerability factors for resistance to exposure treatment in highly fearful chronic pain patients. Previous fear conditioning research showed that healthy individuals scoring relatively high on trait anxiety display sustained fear to safety cues during extinction. In the context of fear of movement-related pain, this intriguing question has been largely neglected so far. Even more importantly, positive psychological traits such as trait positive affect may function as protective factors against the spreading of fear to safe movements and improve exposure treatment outcomes. In this study, healthy participants completed a trait anxiety and trait positive affect questionnaire and underwent acquisition and extinction of fear of movement-related pain using an experimental voluntary movement paradigm. During acquisition, one movement (CS+) was paired with a painful stimulus and another movement was not (CS-). During extinction, the CS+ was no longer reinforced. Results show failure of fear inhibition to the CS- during extinction in healthy individuals scoring relatively high on trait anxiety or relatively low on positive affect. These findings seem to suggest that safety learning is more vulnerable in healthy people with a high anxious disposition and/or relatively lower levels of positive affect. In addition, this is the first study to show that the negative impact of high trait anxiety on fear inhibition to safety cues during extinction can be countered by high levels of positive affect. These findings may have important clinical implications. Both low positive affect and high trait anxiety are associated with impaired fear inhibition to nonpainful movements during fear extinction. Interestingly, high levels of positive affect buffer against the negative impact of trait anxiety. Increasing positive affect during exposure may counter the effects of trait vulnerabilities and improve treatment outcomes. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

Acquisition and extinction of human avoidance behavior: attenuating effect of safety signals and associations with anxiety vulnerabilities.

PubMed

Sheynin, Jony; Beck, Kevin D; Servatius, Richard J; Myers, Catherine E

2014-01-01

While avoidance behavior is often an adaptive strategy, exaggerated avoidance can be detrimental and result in the development of psychopathologies, such as anxiety disorders. A large animal literature shows that the acquisition and extinction of avoidance behavior in rodents depends on individual differences (e.g., sex, strain) and might be modulated by the presence of environmental cues. However, there is a dearth of such reports in human literature, mainly due to the lack of adequate experimental paradigms. In the current study, we employed a computer-based task, where participants control a spaceship and attempt to gain points by shooting an enemy spaceship that appears on the screen. Warning signals predict on-screen aversive events; the participants can learn a protective response to escape or avoid these events. This task has been recently used to reveal facilitated acquisition of avoidance behavior in individuals with anxiety vulnerability due to female sex or inhibited personality. Here, we extended the task to include an extinction phase, and tested the effect of signals that appeared during "safe" periods. Healthy young adults (n = 122) were randomly assigned to a testing condition with or without such signals. Results showed that the addition of safety signals during the acquisition phase impaired acquisition (in females) and facilitated extinction of the avoidance behavior. We also replicated our recent finding of an association between female sex and longer avoidance duration and further showed that females continued to demonstrate more avoidance behavior even on extinction trials when the aversive events no longer occurred. This study is the first to show sex differences on the acquisition and extinction of human avoidance behavior and to demonstrate the role of safety signals in such behavior, highlighting the potential relevance of safety signals for cognitive therapies that focus on extinction learning to treat anxiety symptoms.

Acquisition and Extinction of Human Avoidance Behavior: Attenuating Effect of Safety Signals and Associations with Anxiety Vulnerabilities

PubMed Central

Sheynin, Jony; Beck, Kevin D.; Servatius, Richard J.; Myers, Catherine E.

2014-01-01

While avoidance behavior is often an adaptive strategy, exaggerated avoidance can be detrimental and result in the development of psychopathologies, such as anxiety disorders. A large animal literature shows that the acquisition and extinction of avoidance behavior in rodents depends on individual differences (e.g., sex, strain) and might be modulated by the presence of environmental cues. However, there is a dearth of such reports in human literature, mainly due to the lack of adequate experimental paradigms. In the current study, we employed a computer-based task, where participants control a spaceship and attempt to gain points by shooting an enemy spaceship that appears on the screen. Warning signals predict on-screen aversive events; the participants can learn a protective response to escape or avoid these events. This task has been recently used to reveal facilitated acquisition of avoidance behavior in individuals with anxiety vulnerability due to female sex or inhibited personality. Here, we extended the task to include an extinction phase, and tested the effect of signals that appeared during “safe” periods. Healthy young adults (n = 122) were randomly assigned to a testing condition with or without such signals. Results showed that the addition of safety signals during the acquisition phase impaired acquisition (in females) and facilitated extinction of the avoidance behavior. We also replicated our recent finding of an association between female sex and longer avoidance duration and further showed that females continued to demonstrate more avoidance behavior even on extinction trials when the aversive events no longer occurred. This study is the first to show sex differences on the acquisition and extinction of human avoidance behavior and to demonstrate the role of safety signals in such behavior, highlighting the potential relevance of safety signals for cognitive therapies that focus on extinction learning to treat anxiety symptoms. PMID:25309373

High-affinity α4β2 nicotinic receptors mediate the impairing effects of acute nicotine on contextual fear extinction.

PubMed

Kutlu, Munir Gunes; Holliday, Erica; Gould, Thomas J

2016-02-01

Previously, studies from our lab have shown that while acute nicotine administered prior to training and testing enhances contextual fear conditioning, acute nicotine injections prior to extinction sessions impair extinction of contextual fear. Although there is also strong evidence showing that the acute nicotine's enhancing effects on contextual fear conditioning require high-affinity α4β2 nicotinic acetylcholine receptors (nAChRs), it is unknown which nAChR subtypes are involved in the acute nicotine-induced impairment of contextual fear extinction. In this study, we investigated the effects of acute nicotine administration on contextual fear extinction in knock-out (KO) mice lacking α4, β2 or α7 subtypes of nAChRs and their wild-type (WT) littermates. Both KO and WT mice were first trained and tested for contextual fear conditioning and received a daily contextual extinction session for 4 days. Subjects received intraperitoneal injections of nicotine (0.18 mg/kg) or saline 2-4 min prior to each extinction session. Our results showed that the mice that lack α4 and β2 subtypes of nAChRs showed normal contextual fear extinction but not the acute nicotine-induced impairment while the mice that lack the α7 subtype showed both normal contextual extinction and nicotine-induced impairment of contextual extinction. In addition, control experiments showed that acute nicotine-induced impairment of contextual fear extinction persisted when nicotine administration was ceased and repeated acute nicotine administrations alone did not induce freezing behavior in the absence of context-shock learning. These results clearly demonstrate that high-affinity α4β2 nAChRs are necessary for the effects of acute nicotine on contextual fear extinction. Copyright © 2015 Elsevier Inc. All rights reserved.

High-affinity α4β2 nicotinic receptors mediate the impairing effects of acute nicotine on contextual fear extinction

PubMed Central

Kutlu, Munir Gunes; Holliday, Erica; Gould, Thomas J.

2015-01-01

Previously, studies from our lab have shown that while acute nicotine administered prior to training and testing enhances contextual fear conditioning, acute nicotine injections prior to extinction sessions impair extinction of contextual fear. Although there is also strong evidence showing that the acute nicotine’s enhancing effects on contextual fear conditioning require high-affinity α4β2 nicotinic acetylcholine receptors (nAChRs), it is unknown which nAChR subtypes are involved in the acute nicotine-induced impairment of contextual fear extinction. In this study, we investigated the effects of acute nicotine administration on contextual fear extinction in knock-out (KO) mice lacking α4, β2 or α7 subtypes of nAChRs and their wild-type (WT) littermates. Both KO and WT mice were first trained and tested for contextual fear conditioning and received a daily contextual extinction session for 4 days. Subjects received intraperitoneal injections of nicotine (0.18 mg/kg) or saline 2–4 mins prior to each extinction session. Our results showed that the that mice lack α4 and β2 subtypes of nAChRs showed normal contextual fear extinction but not the acute nicotine-induced impairment while the mice that lack the α7 subtype showed both normal contextual extinction and nicotine-induced impairment of contextual extinction. In addition, control experiments showed that acute nicotine-induced impairment of contextual fear extinction persisted when nicotine administration was ceased and repeated acute nicotine administrations alone did not induce freezing behavior in the absence of context-shock learning. These results clearly demonstrate that high-affinity α4β2 nAChRs are necessary for the effects of acute nicotine on contextual fear extinction. PMID:26688111

Molecular mechanisms underlying formation of long-term reward memories and extinction memories in the honeybee (Apis mellifera)

PubMed Central

2014-01-01

The honeybee (Apis mellifera) has long served as an invertebrate model organism for reward learning and memory research. Its capacity for learning and memory formation is rooted in the ecological need to efficiently collect nectar and pollen during summer to ensure survival of the hive during winter. Foraging bees learn to associate a flower's characteristic features with a reward in a way that resembles olfactory appetitive classical conditioning, a learning paradigm that is used to study mechanisms underlying learning and memory formation in the honeybee. Due to a plethora of studies on appetitive classical conditioning and phenomena related to it, the honeybee is one of the best characterized invertebrate model organisms from a learning psychological point of view. Moreover, classical conditioning and associated behavioral phenomena are surprisingly similar in honeybees and vertebrates, suggesting a convergence of underlying neuronal processes, including the molecular mechanisms that contribute to them. Here I review current thinking on the molecular mechanisms underlying long-term memory (LTM) formation in honeybees following classical conditioning and extinction, demonstrating that an in-depth analysis of the molecular mechanisms of classical conditioning in honeybees might add to our understanding of associative learning in honeybees and vertebrates. PMID:25225299

Sensory generalization and learning about novel colours by poultry chicks.

PubMed

Osorio, Daniel; Ham, Abigail D; Gonda, Zsusanna; Andrew, Richard J

2009-07-01

In nature animals constantly encounter novel stimuli and need to generalize from known stimuli. The animal may then learn about the novel stimulus. Hull (1947) suggested that as they learn animals distinguish knowledge based on direct experience from inference by generalization and in support of this view suggested that if a subject is directly trained to a stimulus subsequent extinction of responses is slower than when the response is based on generalization. Such an effect is also predicted by Bayesian models that relate the rate of learning to uncertainty in the estimate of stimulus value. We find support for this prediction when chicks learn about a novel colour (orange) if the initial evaluation is based on similarity to known colours (red, yellow). Specifically, if an expected food reward is absent the rate of extinction of the response to the novel stimulus exceeds that for the familiar colours. Interestingly, the change in relative preference for novel and familiar stimuli occurs after a delay of an hour. This type of delay has not, to our knowledge, been reported in previous studies of single-trial learning, but given its importance of generalization in natural behaviour this type of learning may have wide relevance.

Dopamine efflux in the nucleus accumbens during within-session extinction, outcome-dependent, and habit-based instrumental responding for food reward.

PubMed

Ahn, Soyon; Phillips, Anthony G

2007-04-01

Dopamine (DA) activity in the nucleus accumbens (NAc) is related to the general motivational effects of rewarding stimuli. Dickinson and colleagues have shown that initial acquisition of instrumental responding reflects action-outcome relationships based on instrumental incentive learning, which establishes the value of an outcome. Given that the sensitivity of responding to outcome devaluation is not affected by NAc lesions, it is unlikely that incentive learning during the action-outcome phase is mediated by DA activity in the NAc. DA efflux in the NAc after limited and extended training was compared on the assumption that comparable changes would be observed during both action-outcome- and habit-based phases of instrumental responding for food. This study also tested the hypothesis that increase in NAc DA activity is correlated with instrumental responding during extinction maintained by a conditioned stimulus paired with food. Rats were trained to lever press for food (random-interval 30 s schedule). On the 5th and 16th day of training, microdialysis samples were collected from the NAc or mediodorsal striatum (a control site for generalized activity) during instrumental responding in extinction and then for food reward, and analyzed for DA content using high performance liquid chromatography. Increase in DA efflux in the NAc accompanied responding for food pellets on both days 5 and 16, with the magnitude of increase significantly enhanced on day 16. DA efflux was also significantly elevated during responding in extinction only on day 16. These results support a role for NAc DA activity in Pavlovian, but not instrumental, incentive learning.

Outcome-Specific Transfer between Predictive and Instrumental Learning Is Unaffected by Extinction but Reversed by Counterconditioning in Human Participants

ERIC Educational Resources Information Center

Rosas, Juan M.; Paredes-Olay, Maria C.; Garcia-Gutierrez, Ana; Espinosa, Juan J.; Abad, Maria J. F.

2010-01-01

Three experiments were conducted to explore the effects of different interference treatments upon outcome-specific transfer from predictive learning to instrumental responding. A computer game was designed in which participants had to defend Andalusia from navy and air-force attacks. Participants learned the relationship between two instrumental…

Impaired Discrimination Learning in Mice Lacking the NMDA Receptor NR2A Subunit

ERIC Educational Resources Information Center

Brigman, Jonathan L.; Feyder, Michael; Saksida, Lisa M.; Bussey, Timothy J.; Mishina, Masayoshi; Holmes, Andrew

2008-01-01

N-Methyl-D-aspartate receptors (NMDARs) mediate certain forms of synaptic plasticity and learning. We used a touchscreen system to assess NR2A subunit knockout mice (KO) for (1) pairwise visual discrimination and reversal learning and (2) acquisition and extinction of an instrumental response requiring no pairwise discrimination. NR2A KO mice…

Prior cocaine exposure disrupts extinction of fear conditioning

PubMed Central

Burke, Kathryn A.; Franz, Theresa M.; Gugsa, Nishan; Schoenbaum, Geoffrey

2008-01-01

Psychostimulant exposure has been shown to cause molecular and cellular changes in prefrontal cortex. It has been hypothesized that these drug-induced changes might affect the operation of prefrontal-limbic circuits, disrupting their normal role in controlling behavior and thereby leading to compulsive drug-seeking. To test this hypothesis, we tested cocaine-treated rats in a fear conditioning, inflation, and extinction task, known to depend on medial prefrontal cortex and amygdala. Cocaine-treated rats conditioned and inflated similar to saline controls but displayed slower extinction learning. These results support the hypothesis that control processes in the medial prefrontal cortex are impaired by cocaine exposure. PMID:16847305

Prior cocaine exposure disrupts extinction of fear conditioning.

PubMed

Burke, Kathryn A; Franz, Theresa M; Gugsa, Nishan; Schoenbaum, Geoffrey

2006-01-01

Psychostimulant exposure has been shown to cause molecular and cellular changes in prefrontal cortex. It has been hypothesized that these drug-induced changes might affect the operation of prefrontal-limbic circuits, disrupting their normal role in controlling behavior and thereby leading to compulsive drug-seeking. To test this hypothesis, we tested cocaine-treated rats in a fear conditioning, inflation, and extinction task, known to depend on medial prefrontal cortex and amygdala. Cocaine-treated rats conditioned and inflated similar to saline controls but displayed slower extinction learning. These results support the hypothesis that control processes in the medial prefrontal cortex are impaired by cocaine exposure.

Pharmacological enhancement of drug cue extinction learning: translational challenges

PubMed Central

Kantak, K.M.; Nic Dhonnchadha, B.Á.

2010-01-01

Augmentation of cue exposure (extinction) therapy with cognitive-enhancing pharmacotherapy may constitute a rational strategy for the clinical management of drug relapse. While certain success has been reported for this form of therapy in anxiety disorders, in this article we highlight several obstacles that may undermine the efficacy of exposure therapy for substance use disorders. We also review translational studies that have evaluated the facilitative effects of the cognitive enhancer D-cycloserine on extinction targeting drug-related cues. Finally, important considerations for the design and implementation of future studies evaluating exposure therapy combined with pharmacotherapy for substance use disorders are discussed. PMID:21272016

Taste-immunosuppression engram: reinforcement and extinction.

PubMed

Niemi, Maj-Britt; Härting, Margarete; Kou, Wei; Del Rey, Adriana; Besedovsky, Hugo O; Schedlowski, Manfred; Pacheco-López, Gustavo

2007-08-01

Several Pavlovian conditioning paradigms have documented the brain's abilities to sense immune-derived signals or immune status, associate them with concurrently relevant extereoceptive stimuli, and reinstate such immune responses on demand. Specifically, the naturalistic relation of food ingestion with its possible immune consequences facilitates taste-immune associations. Here we demonstrate that the saccharin taste can be associated with the immunosuppressive agent cyclosporine A, and that such taste-immune associative learning is subject to reinforcement. Furthermore, once consolidated, this saccharin-immunosuppression engram is resistant to extinction when avoidance behavior is assessed. More importantly, the more this engram is activated, either at association or extinction phases, the more pronounced is the conditioned immunosuppression.

AMYGDALA MICROCIRCUITS CONTROLLING LEARNED FEAR

PubMed Central

Duvarci, Sevil; Pare, Denis

2014-01-01

We review recent work on the role of intrinsic amygdala networks in the regulation of classically conditioned defensive behaviors, commonly known as conditioned fear. These new developments highlight how conditioned fear depends on far more complex networks than initially envisioned. Indeed, multiple parallel inhibitory and excitatory circuits are differentially recruited during the expression versus extinction of conditioned fear. Moreover, shifts between expression and extinction circuits involve coordinated interactions with different regions of the medial prefrontal cortex. However, key areas of uncertainty remain, particularly with respect to the connectivity of the different cell types. Filling these gaps in our knowledge is important because much evidence indicates that human anxiety disorders results from an abnormal regulation of the networks supporting fear learning. PMID:24908482

Impaired extinction of fear conditioning after REM deprivation is magnified by rearing in an enriched environment.

PubMed

Hunter, Amy Silvestri

2015-07-01

Evidence from both human and animal studies indicates that rapid eye movement sleep (REM) is essential for the acquisition and retention of information, particularly of an emotional nature. Learning and memory can also be impacted by manipulation of housing condition such as exposure to an enriched environment (EE). This study investigated the effects of REM deprivation and EE, both separately and combined, on the extinction of conditioned fear in rats. Consistent with prior studies, conditioning was enhanced in EE-reared rats and extinction was impaired in REM deprived rats. In addition, rats exposed to both REM deprivation and EE showed the greatest impairment in extinction, with effects persisting through the first two days of extinction training. This study is the first to explore the combination of REM deprivation and EE and suggests that manipulations that alter sleep, particularly REM, can have persisting deleterious effects on emotional memory processing. Copyright © 2015 Elsevier Inc. All rights reserved.

Performing the unexplainable: Implicit task performance reveals individually reliable sequence learning without explicit knowledge

PubMed Central

Sanchez, Daniel J.; Gobel, Eric W.; Reber, Paul J.

2015-01-01

Memory-impaired patients express intact implicit perceptual–motor sequence learning, but it has been difficult to obtain a similarly clear dissociation in healthy participants. When explicit memory is intact, participants acquire some explicit knowledge and performance improvements from implicit learning may be subtle. Therefore, it is difficult to determine whether performance exceeds what could be expected on the basis of the concomitant explicit knowledge. Using a challenging new sequence-learning task, robust implicit learning was found in healthy participants with virtually no associated explicit knowledge. Participants trained on a repeating sequence that was selected randomly from a set of five. On a performance test of all five sequences, performance was best on the trained sequence, and two-thirds of the participants exhibited individually reliable improvement (by chi-square analysis). Participants could not reliably indicate which sequence had been trained by either recognition or recall. Only by expressing their knowledge via performance were participants able to indicate which sequence they had learned. PMID:21169570

Behavioural memory reconsolidation of food and fear memories

PubMed Central

Flavell, Charlotte R.; Barber, David J.; Lee, Jonathan L. C.

2012-01-01

The reactivation of a memory through retrieval can render it subject to disruption or modification through the process of memory reconsolidation. In both humans and rodents, briefly reactivating a fear memory results in effective erasure by subsequent extinction training. Here we show that a similar strategy is equally effective in the disruption of appetitive pavlovian cue–food memories. However, systemic administration of the NMDA receptor partial agonist D-cycloserine under the same behavioural conditions did not potentiate appetitive memory extinction, suggesting that reactivation does not enhance subsequent extinction learning. To confirm that reactivation followed by extinction reflects a behavioural analog of memory reconsolidation, we show that prevention of contextual fear memory reactivation by the LVGCC blocker nimodipine interferes with the amnestic outcome. Therefore, the reconsolidation process can be manipulated behaviourally to disrupt both aversive and appetitive memories. PMID:22009036

Ovariectomy increases the age-induced hyperphosphorylation of Tau at hippocampal CA1.

PubMed

Picazo, O; Espinosa-Raya, J; Briones-Aranda, A; Cerbón, M

2016-11-01

One of the main hallmarks of Alzheimer's disease includes the neurofibrillary tangles formation produced by hyperphosphorylation of the Tau protein, whose expression is putatively regulated by the ovarian hormones estradiol and progesterone. Hippocampus is a brain region that participates in many functions related to learning and memory; in addition, it is abundant in both estradiol and progesterone receptors. In this study, we explore the expression of Tau hyperphosphorylation at hippocampus and the performance of rats in an autoshaping learning task at 5, 10 and 15 months after the ovaries removal. In these animals, ovariectomy was performed at 3 months of age. These data were compared with those derived from intact rats at 8, 13 and 18 months old. A clear decrease in the number of conditioned responses of both intact and ovariectomized rats in the autoshaping learning task was observed. The interaction of both factors confirms that, in this test, learning varies depending on aging and the presence or absence of ovaries. A progressive increase in hippocampal Tau phosphorylation at Ser-396 was observed in either intact or ovariectomized rats. Interestingly, an interaction between the analyzed factors shows that such hyperphosphorylation was potentiated by the absence of ovaries. These results emphasize the importance of aging and the lack of ovarian hormones for an associative learning test and for the expression of one of the most important hallmarks of Alzheimer's disease.

Spaced sessions of avoidance extinction reduce spontaneous recovery and promote infralimbic cortex activation.

PubMed

Tapias-Espinosa, Carles; Kádár, Elisabet; Segura-Torres, Pilar

2018-01-15

Extinction-based therapies (EBT) are the psychological treatments of choice for certain anxiety disorders, such as post-traumatic stress disorder. However, some patients relapse and suffer spontaneous recovery (SR) of anxiety symptoms and persistence of avoidance behaviour, which underlines the need for improving EBT. In rats, recent evidence has highlighted the relevance of the temporal distribution of extinction sessions in reducing SR of auditory fear conditioning, although it has seldom been studied in procedures involving proactive avoidance responses, such as two-way active avoidance conditioning (TWAA). We examined whether the temporal distribution of two extinction sessions separated by 24h or 7days (contiguous versus spaced extinction paradigms, respectively), influences SR after 28days of a TWAA task. c-Fos expression, as a marker of neuronal activation, was also measured by immunohistochemistry 90min after the SR test in the amygdala and the medial prefrontal cortex. The temporal distribution of extinction sessions did not affect the degree of extinction learning. However, only the rats that underwent the 7-day spaced extinction paradigm maintained the level of extinction in the long term, showing no SR in TWAA. This behavioural finding was consistent with a greater number of c-Fos-labelled neurons in the infralimbic cortex in the 7-day group, and in the Lateral and Central nuclei of the amygdala in the 24-hour group. These findings show that a time-spaced extinction paradigm reduces the spontaneous recovery of active avoidance behaviour, and that this behavioural advantage appears to be related to the activation of the infralimbic cortex. Copyright © 2017 Elsevier B.V. All rights reserved.

Attenuating fearful memories: effect of cued extinction on intrusions.

PubMed

Marks, Elizabeth H; Zoellner, Lori A

2014-12-01

Exposure-based therapies for posttraumatic stress disorder are thought to reduce intrusive memories through extinction processes. Methods that enhance extinction may translate to improved treatment. Rat research suggests retrieving a memory via a conditioned stimulus (CS) cue, and then modifying the retrieved memory within a specific reconsolidation window may enhance extinction. In humans, studies (e.g., Kindt & Soeter, 2013; Schiller et al., 2010) using basic learning paradigms show discrepant findings. Using a distressing film paradigm, participants (N = 148) completed fear acquisition and extinction. At extinction, they were randomized to 1 of 3 groups: CS cue within reconsolidation window, CS cue outside window, or non-CS cue within window. Intrusions were assessed 24 hr after extinction. Participants receiving the CS cue and completing extinction within the reconsolidation window had more intrusions (M = 2.40, SD = 2.54) than those cued outside (M = 1.65, SD = 1.70) or those receiving a non-CS cue (M = 1.24, SD = 1.26), F(2, 145) = 4.52, p = .01, d = 0.55. Consistent with the reconsolidation hypothesis, presenting a CS cue does appear to activate a specific period of time during which a memory can be updated. However, the CS cue caused increased, rather than decreased, frequency of intrusions. Understanding parameters of preextinction cueing may help us better understand reconsolidation as a potential memory updating mechanism.

Extinction of Contextual Fear with Timed Exposure to Enriched Environment: A Differential Effect

PubMed Central

Hegde, Preethi; O'Mara, Shane; Laxmi, Thenkanidiyoor Rao

2017-01-01

Background Extinction of fear memory depends on the environmental and emotional cues. Furthermore, consolidation of extinction is also dependent on the environmental exposure. But, the relationship of the time of the exposure to a variety of environmental cues is not well known. The important region involved in facilitation of extinction of fear memory is through diversion of the flow of information leaving the lateral nucleus of amygdala. Purpose The study aimed to address a question to explain how these brain regions react to environmental stimulation during the retention and extinction of fear memory. Methods An enriched environment (EE) is assumed to mediate extinction of fear memory, we examined the apparent discrepancy between the effects of defensive response, the freezing behavior induced by Pavlovian classical fear conditioning by subjecting them to variance in the timing to EE. The different timing of EE exposure was 10 days of EE either before fear conditioning and/or after extinction training to the rats. The local field potentials was recorded from CA1 hippocampus, lateral nucleus of amygdala and infralimbic region of medial prefrontal cortex (mPFC) during the fear learning and extinction from the control rats and rats exposed to EE before and after fear conditioning. Results Exposure to EE before the fear conditioning and after extinction training was more effective in the extinction fear memory. In addition, we also found switching from exploratory locomotion to freezing during retention of contextual fear memory which was associated with decreased theta power and reduced synchronized theta oscillations in CA1-hippocampus, lateral nucleus of amygdala, and infralimbic region of mPFC. Conclusion Thus, we propose that the timing of exposure to EE play a key role in the extinction of fear memory. PMID:28588364

Extinction, reacquisition, and rapid forgetting of eyeblink conditioning in developing rats

PubMed Central

Freeman, John H.

2014-01-01

Eyeblink conditioning is a well-established model for studying the developmental neurobiology of associative learning and memory. However, age differences in extinction and subsequent reacquisition have yet to be studied using this model. The present study examined extinction and reacquisition of eyeblink conditioning in developing rats. In Experiment 1, post-natal day (P) 17 and 24 rats were trained to a criterion of 80% conditioned responses (CRs) using stimulation of the middle cerebellar peduncle (MCP) as a conditioned stimulus (CS). Stimulation CS-alone extinction training commenced 24 h later, followed by reacquisition training after the fourth extinction session. Contrary to expected results, rats trained starting on P17 showed significantly fewer CRs to stimulation CS-alone presentations relative to P24s, including fewer CRs as early as the first block of extinction session 1. Furthermore, the P17 group was slower to reacquire following extinction. Experiment 2 was run to determine the extent to which the low CR percentage observed in P17s early in extinction reflected rapid forgetting versus rapid extinction. Twenty-four hours after reaching criterion, subjects were trained in a session split into 50 stimulation CS-unconditioned stimulus paired trials followed immediately by 50 stimulation CS-alone trials. With this “immediate” extinction protocol, CR percentages during the first block of stimulation CS-alone presentations were equivalent to terminal acquisition levels at both ages but extinction was more rapid in the P17 group. These findings indicate that forgetting is observed in P17 relative to P24 rats 24 h following acquisition. The forgetting in P17 rats has important implications for the neurobiological mechanisms of memory in the developing cerebellum. PMID:25403458

Discriminative evaluative conditioning in the long-term after severe accidental injury.

PubMed

Oe, Misari; Schumacher, Sonja; Schnyder, Ulrich; Mueller-Pfeiffer, Christoph; Wilhelm, Frank H; Kuelen, Eveline; Martin-Soelch, Chantal

2016-06-30

Impairments in classical fear conditioning and deficits in discriminative learning are observed in posttraumatic stress disorder (PTSD). However, it is unknown whether similar impairments can be found with types of discriminative learning other than classical conditioning, such as evaluative conditioning (EC), in which the valence of a stimulus can be transferred to other stimuli. In this study, we investigated whether EC is also influenced by traumatic experiences independently of presence of PTSD. We tested 14 accident survivors with remitted PTSD, 14 survivors without PTSD, and 16 non-trauma controls. We used behavioral measures, psychophysiological indicators, and subjective ratings for tasks. General effects of learning were observed across groups and conditioning/extinction. Trauma controls had slower reaction times (RTs) to the aversive conditioned stimulus compared to appetitive conditioned and neutral stimuli, as well as slower RTs and increased accuracy during conditioning than during extinction. Remitted PTSD participants showed opposite results, demonstrating decreased accuracy and slower RTs during conditioning as compared to during extinction. No discriminative effect was found in the non-trauma controls and the remitted PTSD participants. These results suggest that a traumatic experience influences EC, and that this influence differs between individuals who have and have not developed PTSD after traumatic exposure. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Testing the disgust conditioning theory of food-avoidance in adolescents with recent onset anorexia nervosa.

PubMed

Hildebrandt, Tom; Grotzinger, Andrew; Reddan, Marianne; Greif, Rebecca; Levy, Ifat; Goodman, Wayne; Schiller, Daniela

2015-08-01

Anorexia nervosa is characterized by chronic food avoidance that is resistant to change. Disgust conditioning offers one potential unexplored mechanism for explaining this behavioral disturbance because of its specific role in facilitating food avoidance in adaptive situations. A food based reversal learning paradigm was used to study response flexibility in 14 adolescent females with restricting subtype anorexia nervosa (AN-R) and 15 healthy control (HC) participants. Expectancy ratings were coded as a behavioral measure of flexibility and electromyography recordings from the levator labii (disgust), zygomaticus major (pleasure), and corrugator (general negative affect) provided psychophysiological measures of emotion. Response inflexibility was higher for participants with AN-R, as evidenced by lower extinction and updated expectancy ratings during reversal. EMG responses to food stimuli were predictive of both extinction and new learning. Among AN-R patients, disgust specific responses to food were associated with impaired extinction, as were elevated pleasure responses to the cued absence of food. Disgust conditioning appears to influence food learning in acutely ill patients with AN-R and may be maintained by counter-regulatory acquisition of a pleasure response to food avoidance and an aversive response to food presence. Developing strategies to target disgust may improve existing interventions for patients with AN. Copyright © 2015 Elsevier Ltd. All rights reserved.

New learning and unlearning: strangers or accomplices in threat memory attenuation?

PubMed Central

Clem, Roger L.; Schiller, Daniela

2016-01-01

To achieve greatest efficacy, therapies for attenuating fear and anxiety should preclude the re-emergence of emotional responses. Of relevance to this aim, preclinical models of threat memory reduction are considered to engage one of two discrete neural processes: either establishment of a new behavioral response that competes with, and thereby temporarily interferes with expression of, an intact threat memory (new learning), or one which modifies and thereby disrupts an intact threat memory (unlearning). We contend that a strict dichotomy of new learning and unlearning does not provide a compelling explanation for current data. Instead, we suggest the evidence warrants consideration of alternative models that assume cooperation rather than competition between formation of new cellular traces and the modification of preexisting ones. PMID:27079843

Medial prefrontal cortex involvement in the expression of extinction and ABA renewal of instrumental behavior for a food reinforcer.

PubMed

Eddy, Meghan C; Todd, Travis P; Bouton, Mark E; Green, John T

2016-02-01

Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of responding for a food reinforcer. The role of the medial prefrontal cortex in renewal in the original conditioning context may depend in part on control over excitatory context-response or context-(response-outcome) relations that might be learned in acquisition. The role of the vmPFC in expression of extinction may depend on its control over inhibitory context-response or context-(response-outcome) relations that are learned in extinction. Copyright © 2015 Elsevier Inc. All rights reserved.

Developmental differences in aversive conditioning, extinction, and reinstatement: A study with children, adolescents, and adults.

PubMed

Waters, Allison M; Theresiana, Cindy; Neumann, David L; Craske, Michelle G

2017-07-01

This study investigated developmental differences in aversive conditioning, extinction, and reinstatement (i.e., the recovery of conditioned aversive associations following reexposure to the unconditioned stimulus [US] post-extinction). This study examined these mechanisms in children (M age =8.8years), adolescents (M age =16.1years), and adults (M age =32.3years) using differential aversive conditioning with a geometric shape conditional stimulus (CS+) paired with an aversive sound US and another shape (CS-) presented alone. Following an extinction phase in which both CSs were presented alone, half of the participants in each age group received three US exposures (reinstatement condition) and the other half did not (control condition), followed by all participants completing an extinction retest phase on the same day. Findings indicated (a) significant differences in generalizing aversive expectancies to safe stimuli during conditioning and extinction that persisted during retest in children relative to adults and adolescents, (b) significantly less positive CS reevaluations during extinction that persisted during retest in adolescents relative to adults and children, and (c) reinstatement of US expectancies to the CS+ relative to the CS- in all age groups. Results suggest important differences in stimulus safety learning in children and stimulus valence reevaluation in adolescents relative to adults. Copyright © 2017 Elsevier Inc. All rights reserved.

Impairment of endocannabinoids activity in the dorsolateral striatum delays extinction of behavior in a procedural memory task in rats.

PubMed

Rueda-Orozco, Pavel E; Montes-Rodriguez, Corinne J; Soria-Gomez, Edgar; Méndez-Díaz, Mónica; Prospéro-García, Oscar

2008-07-01

The dorsolateral striatum (DLS) has been implicated in the learning of habits and procedural memories. Extinction of this kind of memories has been poorly studied. The DLS expresses high levels of the cannabinergic receptor one (CB1), and, lately, it has been suggested that the activation of CB1 in this structure is indispensable for long-term depression (LTD) development. We performed experiments in a T-maze and evaluated the effects of intrastriatal and intrahipocampal administration of the CB1 antagonist AM251 on extinction and on c-Fos expression. We also administered anandamide to evaluate if an artificial increase of endocannabinoids facilitates extinction. Our results indicate clearly a dose-response blockade of extinction induced by AM251 injected into the striatum but a facilitation of extinction when administered into the hippocampus. Anandamide did not induce any observable changes. AM251 effects were accompanied by an increase in c-Fos immunoreactivity in the DLS and its decrease in the hippocampal region, suggesting that the activation of CB1 in the striatum is necessary for the extinction of procedural memories. These findings could be important in some neurological conditions, such as obsessive-compulsive disorder in which striatal activity seems to be abnormal.

Incentive memory: evidence the basolateral amygdala encodes and the insular cortex retrieves outcome values to guide choice between goal-directed actions.

PubMed

Parkes, Shauna L; Balleine, Bernard W

2013-05-15

Choice between goal-directed actions is determined by the relative value of their consequences. Such values are encoded during incentive learning and later retrieved to guide performance. Although the basolateral amygdala (BLA) and the gustatory region of insular cortex (IC) have been implicated in these processes, their relative contribution is still a matter of debate. Here we assessed whether these structures interact during incentive learning and retrieval to guide choice. In these experiments, rats were trained on two actions for distinct outcomes after which one of the two outcomes was devalued by specific satiety immediately before a choice extinction test. We first confirmed that, relative to appropriate controls, outcome devaluation recruited both the BLA and IC based on activation of the immediate early gene Arc; however, we found that infusion of the NMDAr antagonist ifenprodil into the BLA only abolished outcome devaluation when given before devaluation. In contrast, ifenprodil infusion into the IC was effective whether made before devaluation or test. We hypothesized that the BLA encodes and the IC retrieves incentive value for choice and, to test this, developed a novel sequential disconnection procedure. Blocking NMDAr activation unilaterally in the BLA before devaluation and then contralaterally in the IC before test abolished selective devaluation. In contrast, reversing the order of these infusions left devaluation intact. These results confirm that the BLA and IC form a circuit mediating the encoding and retrieval of outcome values, with the BLA encoding and the IC retrieving such values to guide choice.

In Search for Boundary Conditions of Reconsolidation: A Failure of Fear Memory Interference

PubMed Central

Schroyens, Natalie; Beckers, Tom; Kindt, Merel

2017-01-01

The presentation of a fear memory cue can result in mere memory retrieval, destabilization of the reactivated memory trace, or the formation of an extinction memory. The interaction between the degree of novelty during reactivation and previous learning conditions is thought to determine the outcome of a reactivation session. This study aimed to evaluate whether contextual novelty can prevent cue-induced destabilization and disruption of a fear memory acquired by non-asymptotic learning. To this end, fear memory was reactivated in a novel context or in the original context of learning, and fear memory reactivation was followed by the administration of propranolol, an amnestic drug. Remarkably, fear memory was not impaired by post-reactivation propranolol administration or extinction training under the usual conditions used in our lab, irrespective of the reactivation context. These unexpected findings are discussed in the light of our current experimental parameters and alleged boundary conditions on memory destabilization. PMID:28469565

Molecular Mechanisms Underlying Formation of Long-Term Reward Memories and Extinction Memories in the Honeybee ("Apis Mellifera")

ERIC Educational Resources Information Center

Eisenhardt, Dorothea

2014-01-01

The honeybee ("Apis mellifera") has long served as an invertebrate model organism for reward learning and memory research. Its capacity for learning and memory formation is rooted in the ecological need to efficiently collect nectar and pollen during summer to ensure survival of the hive during winter. Foraging bees learn to associate a…

Chronic dietary magnesium-L-threonate speeds extinction and reduces spontaneous recovery of a conditioned taste aversion

PubMed Central

Mickley, G. Andrew; Hoxha, Nita; Luchsinger, Joseph L.; Rogers, Morgan M.; Wiles, Nathanael R.

2013-01-01

Elevation of brain magnesium enhances synaptic plasticity and extinction of conditioned fear memories. This experiment examined the generalizability of this phenomenon by studying the effects of a novel magnesium compound, magnesium-L-threonate (MgT), on conditioned taste aversion (CTA) extinction and spontaneous recovery (SR). Adult male Sprague-Dawley rats were maintained on a 23-hour water deprivation cycle and acquired a CTA following the taste of a CS [0.3% saccharin + 16mg/ml MgT (SAC+MgT)] paired with a US [81 mg/kg (i.p.) Lithium Chloride (LiCl)]. Following CTA acquisition, rats drank a water + MgT solution for up to 1 hour/day over the next 31 days. For 14 additional days, some animals continued water + MgT treatment, but others drank water only to allow MgT to be eliminated from the body. We then employed 2 different extinction paradigms: (1) CS-Only (CSO), in which SAC was presented, every-other day, or (2) Explicitly Unpaired (EU), in which both SAC and LiCl were presented, but on alternate days. EU extinction procedures have been shown to speed CTA extinction and reduce spontaneous recovery of the aversion. Throughout extinction, half of the rats in each group continued to drink MgT (now in SAC or supplemental water+MgT solution), whereas the other half drank SAC only/water only until SAC drinking reached ≥ 90% of baseline (asymptotic extinction). Rats receiving MgT just before/during extinction drank less SAC on the first day of extinction suggesting that they had retained a stronger CTA. MgT enhanced the rate of extinction. Furthermore, the MgT-treated rats showed a relatively modest SR of the CTA 30 days later – indicating that the extinction procedure was more effective for these animals. Our data suggest that long-term dietary MgT may enhance the consolidation/retention of a CTA, speed extinction, and inhibit SR of this learned aversion. PMID:23474371

Infralimbic GluN2A-Containing NMDA Receptors Modulate Reconsolidation of Cocaine Self-Administration Memory

PubMed Central

Hafenbreidel, Madalyn; Rafa Todd, Carolynn; Mueller, Devin

2017-01-01

Addiction is characterized by high relapse susceptibility, and relapse can be triggered by drug-associated cues. Cue presentation induces retrieval of the drug-cue memory, which becomes labile and must be reconsolidated into long-term storage. Repeated unpaired cue presentation, however, promotes extinction. Cue-reactivity can be reduced by blocking reconsolidation or facilitating extinction, which are mediated by NMDA receptors (NMDArs). However, the role of NMDArs in either process following self-administration is unclear. Thus, to determine their role in extinction, rats learned to self-administer cocaine before receiving injections of the NMDAr antagonist CPP immediately after four 45-min extinction sessions. During a subsequent 90-min extinction retention test, CPP-treated rats lever pressed less than saline-treated rats indicating that NMDAr blockade facilitated extinction or disrupted drug-cue memory reconsolidation. In addition, infusing CPP into the infralimbic medial prefrontal cortex (IL-mPFC), a structure implicated in extinction, before four 45-min or immediately after four 30min extinction sessions, had similar results during the extinction retention tests. Next, the GluN2A-selective antagonist NVP or GluN2B-selective antagonist Ro25 was infused into IL-mPFC or nucleus accumbens (NAc) shell, another structure implicated in extinction, after four 45-min extinction sessions. Blocking GluN2A-, but not GluN2B-, containing NMDArs, in IL-mPFC or NAc shell reduced lever pressing during the extinction retention tests. Finally, to dissociate reconsolidation from extinction, NVP was infused into IL-mPFC after four 10-min reactivation sessions, which resulted in reduced lever pressing during the retention test. These results indicate that IL-mPFC GluN2A-containing NMDArs modulate reconsolidation, and suggest a novel treatment strategy, as reducing cue reactivity could limit relapse susceptibility. PMID:28042872

Selective loss of dopaminergic neurons in the substantia nigra pars compacta after systemic administration of MPTP facilitates extinction learning.

PubMed

Kinoshita, Ken-ichi; Tada, Yayoi; Muroi, Yoshikage; Unno, Toshihiro; Ishii, Toshiaki

2015-09-15

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). In PD, thinking and retrieval deficits often arise from cognitive impairments. However, the mechanism of cognitive disorders in PD remains unknown. Therefore, we investigated cognitive function in PD model mice produced by intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which specifically destroys the DAergic neurons in the SNpc. We evaluated the cognitive function of MPTP-treated mice (PD mice) using the contextual fear conditioning test. In the test, each experiment consists of three phases: training, re-exposure, and testing. Mice were trained with a foot shock (a weak unconditioned stimulus: 1mA/2s duration, once, or an intense unconditioned stimulus: 2mA/2s duration, twice), and 24h later, mice were re-exposed to the training context for 3min to determine reconsolidation or 30min to determine extinction. The percentage of time spent freezing was measured during the test session as indexes of memory consolidation, reconsolidation, and extinction. Reconsolidation of PD mice occurred normally but memory extinction was facilitated in PD mice compared to control mice. Moreover, memory retention in PD mice was attenuated earlier than in controls following repeated conditioned stimuli every day. PD mice with selective loss of DAergic neurons in the SNpc showed attenuated memory retention, probably via facilitated extinction learning. Copyright © 2015 Elsevier Inc. All rights reserved.

Impacts of the Problem-Based Learning Pedagogy on English Learners' Reading Comprehension, Strategy Use, and Active Learning Attitudes

ERIC Educational Resources Information Center

Lin, Lu-Fang

2017-01-01

This study investigated whether an English reading course integrated with the problem-based learning approach could foster foreign language learners' reading comprehension ability, strategy use, and their active learning attitudes. The pedagogy was featured with the small group scaffolding. Two intact English classes in a Taiwanese university were…

Implicit Learning of Local Context in Autism Spectrum Disorder

ERIC Educational Resources Information Center

Kourkoulou, Anastasia; Leekam, Susan R.; Findlay, John M.

2012-01-01

Although previous research has reported impairments in implicit learning in individuals with ASD, research using one implicit learning paradigm, the contextual cueing task (Chun and Jiang in Cognitive Psychol 36:28-71, 1998), shows evidence of intact ability to integrate spatial contextual information. Using an adaptation of this paradigm, we…

Can fear extinction be enhanced? A review of pharmacological and behavioral findings

PubMed Central

Fitzgerald, Paul J.; Seemann, Jocelyn R.; Maren, Stephen

2014-01-01

There is considerable interest, from both a basic and clinical standpoint, in gaining a greater understanding of how pharmaceutical or behavioral manipulations alter fear extinction in animals. Not only does fear extinction in rodents model exposure therapy in humans, where the latter is a cornerstone of behavioral intervention for anxiety disorders such as post-traumatic stress disorder and specific phobias, but also understanding more about extinction provides basic information into learning and memory processes and their underlying circuitry. In this paper, we briefly review three principal approaches that have been used to modulate extinction processes in animals and humans: a purely pharmacological approach, the more widespread approach of combining pharmacology with behavior, and a purely behavioral approach. The pharmacological studies comprise modulation by: brain derived neurotrophic factor (BDNF), d-cycloserine, serotonergic and noradrenergic drugs, neuropeptides, endocannabinoids, glucocorticoids, histone deacetylase (HDAC) inhibitors, and others. These studies strongly suggest that extinction can be modulated by drugs, behavioral interventions, or their combination, although not always in a lasting manner. We suggest that pharmacotherapeutic manipulations provide considerable promise for promoting effective and lasting fear reduction in individuals with anxiety disorders. PMID:24374101

Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle

PubMed Central

Feltenstein, Matthew W.; See, Ronald E.

2007-01-01

Previous studies have reported sex and estrous cycle dependent differences in the reinstatement of cocaine-seeking triggered by cocaine injections or drug-paired cues. However, the relationship between estradiol or progesterone levels and cocaine-seeking in a reinstatement model of relapse has not been explored. Thus, we examined changes in plasma hormone levels during cocaine-taking and cocaine-seeking behaviors in gonadally intact female rats. Rats self-administered cocaine (0.5 mg/kg/infusion) during daily 2-h sessions, followed by extinction. For reinstatement, cocaine (0, 5, or 10 mg/kg, i.p.) was administered 30 min prior to testing. Vaginal smears and blood samples were collected prior to and during chronic cocaine self-administration, extinction, and reinstatement testing. Relative to nonestrous females, females in estrus showed greater responding during self-administration, extinction, and during cocaine-primed reinstatement. The highest progesterone levels were noted at the time of lowest cocaine-seeking (proestrus) and the lowest levels of progesterone occurred at the time of highest cocaine-seeking (estrus). In contrast, plasma estradiol levels did not show any clear pattern with cocaine-seeking. These data from an animal model of relapse supports recent clinical evidence that progesterone reduces subjective craving in cocaine-dependent women. Overall, these results suggest that progesterone administration may be a useful intervention for reducing the incidence of relapse. PMID:17240083

Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle.

PubMed

Feltenstein, Matthew W; See, Ronald E

2007-07-10

Previous studies have reported sex and estrous cycle-dependent differences in the reinstatement of cocaine-seeking triggered by cocaine injections or drug-paired cues. However, the relationship between estradiol or progesterone levels and cocaine-seeking in a reinstatement model of relapse has not been explored. Thus, we examined changes in plasma hormone levels during cocaine-taking and -seeking behaviors in gonadally intact female rats. Rats self-administered cocaine (0.5mg/kg infusion) during daily 2-h sessions, followed by extinction. For reinstatement, cocaine (0, 5, or 10mg/kg, i.p.) was administered 30 min prior to testing. Vaginal smears and blood samples were collected prior to and during chronic cocaine self-administration, extinction, and reinstatement testing. Relative to non-estrous females, females in estrus showed greater responding during self-administration, extinction, and during cocaine-primed reinstatement. The highest progesterone levels were noted at the time of lowest cocaine-seeking (proestrus) and the lowest levels of progesterone occurred at the time of highest cocaine-seeking (estrus). In contrast, plasma estradiol levels did not show any clear pattern with cocaine-seeking. These data from an animal model of relapse supports recent clinical evidence that progesterone reduces subjective craving in cocaine-dependent women. Overall, these results suggest that progesterone administration may be a useful intervention for reducing the incidence of relapse.

Prepared Stimuli Enhance Aversive Learning without Weakening the Impact of Verbal Instructions

ERIC Educational Resources Information Center

Atlas, Lauren Y.; Phelps, Elizabeth A.

2018-01-01

Fear-relevant stimuli such as snakes and spiders are thought to capture attention due to evolutionary significance. Classical conditioning experiments indicate that these stimuli accelerate learning, while instructed extinction experiments suggest they may be less responsive to instructions. We manipulated stimulus type during instructed aversive…

Animal Models of Fear Relapse

PubMed Central

Goode, Travis D.; Maren, Stephen

2014-01-01

Whereas fear memories are rapidly acquired and enduring over time, extinction memories are slow to form and are susceptible to disruption. Consequently, behavioral therapies that involve extinction learning (e.g., exposure therapy) often produce only temporary suppression of fear and anxiety. This review focuses on the factors that are known to influence the relapse of extinguished fear. Several phenomena associated with the return of fear after extinction are discussed, including renewal, spontaneous recovery, reacquisition, and reinstatement. Additionally, this review describes recent work, which has focused on the role of psychological stress in the relapse of extinguished fear. Recent developments in behavioral and pharmacological research are examined in light of treatment of pathological fear in humans. PMID:25225304

Activation of the hypothalamic-pituitary-adrenal axis in lithium-induced conditioned taste aversion learning.

PubMed

Jahng, Jeong Won; Lee, Jong-Ho

2015-12-05

Intraperitoneal injections (ip) of lithium chloride at large doses induce c-Fos expression in the brain regions implicated in conditioned taste aversion (CTA) learning, and also activate the hypothalamic-pituitary-adrenal (HPA) axis and increase the plasma corticosterone levels in rats. A pharmacologic treatment blunting the lithium-induced c-Fos expression in the brain regions, but not the HPA axis activation, induced CTA formation. Synthetic glucocorticoids at conditioning, but not glucocorticoid antagonist, attenuated the lithium-induced CTA acquisition. The CTA acquisition by ip lithium was not affected by adrenalectomy regardless of basal corticosterone supplement, but the extinction was delayed in the absence of basal corticosterone. Glucocorticoids overloading delayed the extinction memory formation of lithium-induced CTA. ip lithium consistently induced the brain c-Fos expression, the HPA activation and CTA formation regardless of the circadian activation of the HPA axis. Intracerebroventricular (icv) injections of lithium at day time also increased the brain c-Fos expression, activated the HPA axis and induced CTA acquisition. However, icv lithium at night, when the HPA axis shows its circadian activation, did not induce CTA acquisition nor activate the HPA axis, although it increased the brain c-Fos expression. These results suggest that the circadian activation of the HPA axis may affect central, but not peripheral, effect of lithium in CTA learning in rats, and the HPA axis activation may be necessary for the central effect of lithium in CTA formation. Also, glucocorticoids may be required for a better extinction; however, increased glucocorticoids hinder both the acquisition and the extinction of lithium-induced CTA. Copyright © 2015. Published by Elsevier B.V.

Individual differences in social and non-social behaviors in domestic dogs (Canis familiaris) during the acquisition, extinction and reacquisition of a problem solving task.

PubMed

Shimabukuro, Carolina; Putrino, Natalia; Helbling, Julia; Tognetti, Sandra; Bentosela, Mariana

2015-04-01

Dogs are able to solve different problems by trial and error learning, but it seems that they cannot understand the means-end connection. Some studies suggest that dogs' performance is influenced by their breed and by the level of familiarity with the person they interact with. In our study, we assess individual differences in both social and non-social responses in a problem-solving task during the acquisition, extinction, and reacquisition phases. In order to investigate the effect of familiarity, in the first experiment, the human present during the task was either a familiar (the dog's owner) or unfamiliar person. In the second experiment, we compared breeds (Retrievers and Shepherds) that had previously shown differences in a communicative task. The results revealed that all groups learned the task and became more efficient in the acquisition trials. These non-social responses diminished during extinction, where an increase in social responses was observed. With regard to individual differences, dogs were more persistent in searching the reward during the second extinction trial when the owner was present (in contrast with a stranger), and also looked longer at the unfamiliar person at the beginning of the acquisition trial. On the other hand, Retrievers showed greater social motivation during reacquisition and Shepherds picked up more bones during the third acquisition trial, thus suggesting a more persistent search of the reward. These findings highlight the relevance of studying different learning schedules as well as individual differences in problem-solving ability so as to improve selection and training techniques. Copyright © 2015 Elsevier B.V. All rights reserved.

Involvement of DNA methylation in memory processing in the honey bee.

PubMed

Lockett, Gabrielle A; Helliwell, Paul; Maleszka, Ryszard

2010-08-23

DNA methylation, an important and evolutionarily conserved epigenetic mechanism, is implicated in learning and memory processes in vertebrates, but its role in behaviour in invertebrates is unknown. We examined the role of DNA methylation in memory in the honey bee using an appetitive Pavlovian olfactory discrimination task, and by assessing the expression of DNA methyltransferase3, a key driver of epigenetic reprogramming. Here we report that DNA methyltransferase inhibition reduces acquisition retention and alters the extinction depending on treatment time, and DNA methyltransferase3 is upregulated after training. Our findings add to the understanding of epigenetic mechanisms in learning and memory, extending known roles of DNA methylation to appetitive and extinction memory, and for the first time implicate DNA methylation in memory in invertebrates.

Behavioral interventions to eliminate fear responses.

PubMed

Yue, Jingli; Shi, Le; Lin, Xiao; Khan, Muhammad Zahid; Shi, Jie; Lu, Lin

2018-05-07

Fear memory underlies anxiety-related disorders, including posttraumatic stress disorder (PTSD). PTSD is a fear-based disorder, characterized by difficulties in extinguishing the learned fear response and maintaining extinction. Currently, the first-line treatment for PTSD is exposure therapy, which forms an extinction memory to compete with the original fear memory. However, the extinguished fear often returns under numerous circumstances, suggesting that novel methods are needed to eliminate fear memory or facilitate extinction memory. This review discusses research that targeted extinction and reconsolidation to manipulate fear memory. Recent studies indicate that sleep is an active state that can regulate memory processes. We also discuss the influence of sleep on fear memory. For each manipulation, we briefly summarize the neural mechanisms that have been identified in human studies. Finally, we highlight potential limitations and future directions in the field to better translate existing interventions to clinical settings.

Virtual Reality-Enhanced Extinction of Phobias and Post-Traumatic Stress.

PubMed

Maples-Keller, Jessica L; Yasinski, Carly; Manjin, Nicole; Rothbaum, Barbara Olasov

2017-07-01

Virtual reality (VR) refers to an advanced technological communication interface in which the user is actively participating in a computer-generated 3-dimensional virtual world that includes computer sensory input devices used to simulate real-world interactive experiences. VR has been used within psychiatric treatment for anxiety disorders, particularly specific phobias and post-traumatic stress disorder, given several advantages that VR provides for use within treatment for these disorders. Exposure therapy for anxiety disorder is grounded in fear-conditioning models, in which extinction learning involves the process through which conditioned fear responses decrease or are inhibited. The present review will provide an overview of extinction training and anxiety disorder treatment, advantages for using VR within extinction training, a review of the literature regarding the effectiveness of VR within exposure therapy for specific phobias and post-traumatic stress disorder, and limitations and future directions of the extant empirical literature.

The partial-reinforcement extinction effect and the contingent-sampling hypothesis.

PubMed

Hochman, Guy; Erev, Ido

2013-12-01

The partial-reinforcement extinction effect (PREE) implies that learning under partial reinforcements is more robust than learning under full reinforcements. While the advantages of partial reinforcements have been well-documented in laboratory studies, field research has failed to support this prediction. In the present study, we aimed to clarify this pattern. Experiment 1 showed that partial reinforcements increase the tendency to select the promoted option during extinction; however, this effect is much smaller than the negative effect of partial reinforcements on the tendency to select the promoted option during the training phase. Experiment 2 demonstrated that the overall effect of partial reinforcements varies inversely with the attractiveness of the alternative to the promoted behavior: The overall effect is negative when the alternative is relatively attractive, and positive when the alternative is relatively unattractive. These results can be captured with a contingent-sampling model assuming that people select options that provided the best payoff in similar past experiences. The best fit was obtained under the assumption that similarity is defined by the sequence of the last four outcomes.

Learned together, extinguished apart: reducing fear to complex stimuli

PubMed Central

Jones, Carolyn E.; Ringuet, Stephanie; Monfils, Marie-H.

2013-01-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window attenuates fear responding and prevents the return of fear in pure tone Pavlovian fear conditioning. Here we sought to examine whether this effect also applies to a more complex fear memory. First, we show that after fear conditioning to the simultaneous presentation of a tone and a light (T+L) coterminating with a shock, the compound memory that ensues is more resistant to fear extinction than simple tone-shock pairings. Next, we demonstrate that the compound memory can be disrupted by interrupting the reconsolidation of the two individual components using a sequential retrieval+extinction paradigm, provided the stronger compound component is retrieved first. These findings provide insight into how compound memories are encoded, and could have important implications for PTSD treatment. PMID:24241750

Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors

PubMed Central

Zhang, D; Wang, X; Wang, B; Garza, J C; Fang, X; Wang, J; Scherer, P E; Brenner, R; Zhang, W; Lu, X-Y

2017-01-01

Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD. PMID:27137743

Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors.

PubMed

Zhang, D; Wang, X; Wang, B; Garza, J C; Fang, X; Wang, J; Scherer, P E; Brenner, R; Zhang, W; Lu, X-Y

2017-07-01

Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD.

Impaired contextual modulation of memories in PTSD: an fMRI and psychophysiological study of extinction retention and fear renewal.

PubMed

Garfinkel, Sarah N; Abelson, James L; King, Anthony P; Sripada, Rebecca K; Wang, Xin; Gaines, Laura M; Liberzon, Israel

2014-10-01

Post-traumatic stress disorder (PTSD) patients display pervasive fear memories, expressed indiscriminately. Proposed mechanisms include enhanced fear learning and impaired extinction or extinction recall. Documented extinction recall deficits and failure to use safety signals could result from general failure to use contextual information, a hippocampus-dependent process. This can be probed by adding a renewal phase to standard conditioning and extinction paradigms. Human subjects with PTSD and combat controls were conditioned (skin conductance response), extinguished, and tested for extinction retention and renewal in a scanner (fMRI). Fear conditioning (light paired with shock) occurred in one context, followed by extinction in another, to create danger and safety contexts. The next day, the extinguished conditioned stimulus (CS+E) was re-presented to assess extinction recall (safety context) and fear renewal (danger context). PTSD patients showed impaired extinction recall, with increased skin conductance and heightened amygdala activity to the extinguished CS+ in the safety context. However, they also showed impaired fear renewal; in the danger context, they had less skin conductance response to CS+E and lower activity in amygdala and ventral-medial prefrontal cortex compared with combat controls. Control subjects displayed appropriate contextual modulation of memory recall, with extinction (safety) memory prevailing in the safety context, and fear memory prevailing in the danger context. PTSD patients could not use safety context to sustain suppression of extinguished fear memory, but they also less effectively used danger context to enhance fear. They did not display globally enhanced fear expression, but rather showed a globally diminished capacity to use contextual information to modulate fear expression. Copyright © 2014 the authors 0270-6474/14/3413435-09$15.00/0.

Age differences in fear retention and extinction in male Sprague-Dawley rats: Effects of ethanol challenge during conditioning

PubMed Central

Broadwater, Margaret; Spear, Linda P.

2013-01-01

Pavlovian fear conditioning is an ideal model to investigate how learning and memory are influenced by alcohol use during adolescence because the neural mechanisms involved have been studied extensively. In Exp 1, adolescent and adult male Sprague-Dawley rats were non-injected or injected with saline, 1 or 1.5 g/kg ethanol intraperitoneally 10 minutes prior to tone or context conditioning. Twenty-four hours later, animals were tested for tone or context retention and extinction, with examination of extinction retention conducted 24 hours thereafter. In Exp 2, a context extinction session was inserted between the tone conditioning and the tone fear retention/extinction days to reduce pre-CS baseline freezing levels at test. Basal levels of acquisition, fear retention, extinction, and extinction retention after tone conditioning were similar between adolescent and adult rats. In contrast adolescents showed faster context extinction than adults, while again not differing from adults during context acquisition, retention or extinction retention. In terms of ethanol effects, adolescents were less sensitive to ethanol-induced context retention deficits than adults. No age differences emerged in terms of tone fear retention, with ethanol disrupting tone fear retention at both ages in Exp1, but at neither age in Exp 2, a difference seemingly due to group differences in pre-CS freezing during tone testing in Exp 1, but not Exp 2. These results suggest that age differences in the acute effects of ethanol on cognitive function are task-specific, and provide further evidence for age differences cognitive functioning in a task thought to be hippocampally-related. PMID:23810415

Reciprocal Interaction of Dendrite Geometry and Nuclear Calcium-VEGFD Signaling Gates Memory Consolidation and Extinction.

PubMed

Hemstedt, Thekla J; Bengtson, C Peter; Ramírez, Omar; Oliveira, Ana M M; Bading, Hilmar

2017-07-19

Nuclear calcium is an important signaling end point in synaptic excitation-transcription coupling that is critical for long-term neuroadaptations. Here, we show that nuclear calcium acting via a target gene, VEGFD, is required for hippocampus-dependent fear memory consolidation and extinction in mice. Nuclear calcium-VEGFD signaling upholds the structural integrity and complexity of the dendritic arbor of CA1 neurons that renders those cells permissive for the efficient generation of synaptic input-evoked nuclear calcium transients driving the expression of plasticity-related genes. Therefore, the gating of memory functions rests on the reciprocally reinforcing maintenance of an intact dendrite geometry and a functional synapse-to-nucleus communication axis. In psychiatric and neurodegenerative disorders, therapeutic application of VEGFD may help to stabilize dendritic structures and network connectivity, which may prevent cognitive decline and could boost the efficacy of extinction-based exposure therapies. SIGNIFICANCE STATEMENT This study uncovers a reciprocal relationship between dendrite geometry, the ability to generate nuclear calcium transients in response to synaptic inputs, and the subsequent induction of expression of plasticity-related and dendritic structure-preserving genes. Insufficient nuclear calcium signaling in CA1 hippocampal neurons and, consequently, reduced expression of the nuclear calcium target gene VEGFD, a dendrite maintenance factor, leads to reduced-complexity basal dendrites of CA1 neurons, which severely compromises the animals' consolidation of both memory and extinction memory. The structure-protective function of VEGFD may prove beneficial in psychiatric disorders as well as neurodegenerative and aging-related conditions that are associated with loss of neuronal structures, dysfunctional excitation-transcription coupling, and cognitive decline. Copyright © 2017 the authors 0270-6474/17/376946-10$15.00/0.

A Psychophysiologic Study of Weakening Traumatic Combat Memories with Post-Reactivation Propranolol

DTIC Science & Technology

2011-06-01

administration [5], gene knockout [6], interference by new learning [4;7]; and manipulations of kinase activity [8;9]. The amnesia induced by blocking...reconsolidation can be double- dissociated from extinction [10;11], and it is distinct from extinction in that it can be made to occur even when a... Dissociable stages of human memory consolidation and reconsolidation. Nature 2003 Oct 9;425(6958):616-20. [8] Duvarci S, Nader K, Ledoux JE. Activation of

Eyeblink conditioning in unmedicated schizophrenia patients: A positron emission tomography study

PubMed Central

Parker, Krystal L.; Andreasen, Nancy C.; Liu, Dawei; Freeman, John H.; O’Leary, Daniel S.

2014-01-01

Previous studies suggest that patients with schizophrenia exhibit dysfunctions in a widely distributed circuit—the cortico-cerebellar-thalamic-cortical circuit, or CCTCC—and that this may explain the multiple cognitive deficits observed in the disorder. This study uses positron emission tomography (PET) with O15 H2O to measure regional cerebral blood flow (rCBF) in response to a classic test of cerebellar function, the associative learning that occurs during eyeblink conditioning, in a sample of 20 unmedicated schizophrenia patients and 20 closely matched healthy controls. The PET paradigm examined three phases of acquisition and extinction (early, middle and late). The patients displayed impaired behavioral performance during both acquisition and extinction. The imaging data indicate that, compared to the control subjects, the patients displayed decreases in rCBF in all three components of the CCTCC during both acquisition and extinction. Specifically, patients had less rCBF in the middle and medial frontal lobes, anterior cerebellar lobules I/V and VI, as well as the thalamus during acquisition and although similar areas were found in the frontal lobe, ipsilateral cerebellar lobule IX showed consistently less activity in patients during extinction. Thus this study provides additional support for the hypothesis that patients with schizophrenia have a cognitive dysmetria—an inability to smoothly coordinate many different types of mental activity—that affects even a very basic cognitive task that taps into associative learning. PMID:24090512

Human fear extinction and return of fear using reconsolidation update mechanisms: The contribution of on-line expectancy ratings

PubMed Central

Warren, Victor Taylor; Anderson, Kemp M.; Kwon, Cliffe; Bosshardt, Lauren; Jovanovic, Tanja; Bradley, Bekh; Norrholm, Seth Davin

2015-01-01

Disruption of the reconsolidation of conditioned fear memories has been suggested as a non-pharmacological means of preventing the return of learned fear in human populations. A reconsolidation update paradigm was developed in which a reconsolidation window is opened by a single isolated retrieval trial of a previously reinforced CS+ which is then followed by Extinction Training within that window. However, follow-up studies in humans using multi-methods fear conditioning indices (e.g., fear-potentiated startle, skin conductance, US-expectancy) have failed to replicate the retrieval + extinction effects. In the present study, we further investigated the retrieval + extinction reconsolidation update paradigm by directly comparing the acquisition, extinction, and return of fear-potentiated startle in the absence or presence of US-expectancy measures (using a trial-by-trial response keypad) with and without retrieval of a previously acquired CS-US association. Participants were fear conditioned to two visual cue CS+'s, one of which was presented as a single, isolated retrieval trial before Extinction Training and one that was extinguished as usual. The results show that the inclusion of US-expectancy measures strengthens the CS–US association to provide enhanced fear conditioning and maintenance of fear memories over the experimental sessions. In addition, in the groups that used on-line US-expectancy measures, the retrieval + extinction procedure reduced reinstatement of fear-potentiated startle to both previously reinforced CS+'s, as compared to the extinction as usual group. PMID:24183839

Stressor controllability modulates fear extinction in humans

PubMed Central

Hartley, Catherine A.; Gorun, Alyson; Reddan, Marianne C.; Ramirez, Franchesca; Phelps, Elizabeth A.

2014-01-01

Traumatic events are proposed to play a role in the development of anxiety disorders, however not all individuals exposed to extreme stress experience a pathological increase in fear. Recent studies in animal models suggest that the degree to which one is able to control an aversive experience is a critical factor determining its behavioral consequences. In this study, we examined whether stressor controllability modulates subsequent conditioned fear expression in humans. Participants were randomly assigned to an escapable stressor condition, a yoked inescapable stressor condition, or a control condition involving no stress exposure. One week later, all participants underwent fear conditioning, fear extinction, and a test of extinction retrieval the following day. Participants exposed to inescapable stress showed impaired fear extinction learning and increased fear expression the following day. In contrast, escapable stress improved fear extinction and prevented the spontaneous recovery of fear. Consistent with the bidirectional controllability effects previously reported in animal models, these results suggest that one's degree of control over aversive experiences may be an important factor influencing the development of psychological resilience or vulnerability in humans. PMID:24333646

Age and adolescent social stress effects on fear extinction in female rats.

PubMed

McCormick, C M; Mongillo, D L; Simone, J J

2013-11-01

We previously observed that social instability stress (SS: daily 1 h isolation and change of cage partners for 16 days) in adolescence, but not in adulthood, decreased context and cue memory after fear conditioning in male rats. Effects of stress are typically sex-specific, and so here we investigated adolescent and adult SS effects in females on the strength of acquired contextual and cued fear conditioning, as well as extinction learning, beginning either the day after the stress procedure or four weeks later. For SS in adolescence, SS females spent more time freezing (fear measure) during extinction than did controls, whereas SS in adulthood had no effect on any measure of fear conditioning. The results also indicated an effect of age: females in late adolescence show more rapid extinction of cue and better memory of extinction of context compared to adult females, which may indicate resilience to acute footshock in adolescence. Thus fear circuitry continues to mature into late adolescence, which may underlie the heightened plasticity in response to chronic stressors of adolescents compared to adults.

Intrahippocampal Muscimol Shifts Learning Strategy in Gonadally Intact Young Adult Female Rats

ERIC Educational Resources Information Center

McElroy, Molly W.; Korol, Donna L.

2005-01-01

Learning strategy preferences depend upon circulating estrogen levels, with enhanced hippocampus-sensitive place learning coinciding with elevated estrogen levels. The effects of estrogen on strategy may be mediated by fluctuations in GABAergic function, given that inhibitory tone in the hippocampus is low when estrogen is high. We investigated…

Learning to Program in KPL through Guided Collaboration

ERIC Educational Resources Information Center

Hsiao, Sheng-Che; Lin, Janet Mei-Chuen; Kang, Jiin-Cherng

2011-01-01

A quasi-experiment was conducted at an elementary school to investigate if guided collaboration would facilitate programming learning of 6 graders. Sixty-six students of two intact classes learned to program in KPL (kid's programming language) for 18 weeks during the experiment. One class was randomly assigned to the control group (i.e.,…

Is Implicit Sequence Learning Impaired in Schizophrenia? A Meta-Analysis

ERIC Educational Resources Information Center

Siegert, Richard J.; Weatherall, Mark; Bell, Elliot M.

2008-01-01

Cognition in schizophrenia seems to be characterized by impaired performance on most tests of explicit or declarative learning contrasting with relatively intact performance on most tests of implicit or procedural learning. At the same time there have been conflicting results for studies that have used the Serial Reaction Time (SRT) task to…

The Impact of Individual Differences on E-Learning System Satisfaction: A Contingency Approach

ERIC Educational Resources Information Center

Lu, Hsi-Peng; Chiou, Ming-Jen

2010-01-01

This study investigated the impact of contingent variables on the relationship between four predictors and students' satisfaction with e-learning. Five hundred and twenty-two university students from 10 intact classes engaging in online instruction were asked to answer questionnaires about their learning styles, perceptions of the quality of the…

Visual Associative Learning in Restrained Honey Bees with Intact Antennae

PubMed Central

Dobrin, Scott E.; Fahrbach, Susan E.

2012-01-01

A restrained honey bee can be trained to extend its proboscis in response to the pairing of an odor with a sucrose reward, a form of olfactory associative learning referred to as the proboscis extension response (PER). Although the ability of flying honey bees to respond to visual cues is well-established, associative visual learning in restrained honey bees has been challenging to demonstrate. Those few groups that have documented vision-based PER have reported that removing the antennae prior to training is a prerequisite for learning. Here we report, for a simple visual learning task, the first successful performance by restrained honey bees with intact antennae. Honey bee foragers were trained on a differential visual association task by pairing the presentation of a blue light with a sucrose reward and leaving the presentation of a green light unrewarded. A negative correlation was found between age of foragers and their performance in the visual PER task. Using the adaptations to the traditional PER task outlined here, future studies can exploit pharmacological and physiological techniques to explore the neural circuit basis of visual learning in the honey bee. PMID:22701575

Distribution of living Cupressaceae reflects the breakup of Pangea

PubMed Central

Mao, Kangshan; Milne, Richard I.; Zhang, Libing; Peng, Yanling; Liu, Jianquan; Thomas, Philip; Mill, Robert R.; S. Renner, Susanne

2012-01-01

Most extant genus-level radiations in gymnosperms are of Oligocene age or younger, reflecting widespread extinction during climate cooling at the Oligocene/Miocene boundary [∼23 million years ago (Ma)]. Recent biogeographic studies have revealed many instances of long-distance dispersal in gymnosperms as well as in angiosperms. Acting together, extinction and long-distance dispersal are likely to erase historical biogeographic signals. Notwithstanding this problem, we show that phylogenetic relationships in the gymnosperm family Cupressaceae (162 species, 32 genera) exhibit patterns expected from the Jurassic/Cretaceous breakup of Pangea. A phylogeny was generated for 122 representatives covering all genera, using up to 10,000 nucleotides of plastid, mitochondrial, and nuclear sequence per species. Relying on 16 fossil calibration points and three molecular dating methods, we show that Cupressaceae originated during the Triassic, when Pangea was intact. Vicariance between the two subfamilies, the Laurasian Cupressoideae and the Gondwanan Callitroideae, occurred around 153 Ma (124–183 Ma), when Gondwana and Laurasia were separating. Three further intercontinental disjunctions involving the Northern and Southern Hemisphere are coincidental with or immediately followed the breakup of Pangea. PMID:22550176

Distribution of living Cupressaceae reflects the breakup of Pangea.

PubMed

Mao, Kangshan; Milne, Richard I; Zhang, Libing; Peng, Yanling; Liu, Jianquan; Thomas, Philip; Mill, Robert R; Renner, Susanne S

2012-05-15

Most extant genus-level radiations in gymnosperms are of Oligocene age or younger, reflecting widespread extinction during climate cooling at the Oligocene/Miocene boundary [∼23 million years ago (Ma)]. Recent biogeographic studies have revealed many instances of long-distance dispersal in gymnosperms as well as in angiosperms. Acting together, extinction and long-distance dispersal are likely to erase historical biogeographic signals. Notwithstanding this problem, we show that phylogenetic relationships in the gymnosperm family Cupressaceae (162 species, 32 genera) exhibit patterns expected from the Jurassic/Cretaceous breakup of Pangea. A phylogeny was generated for 122 representatives covering all genera, using up to 10,000 nucleotides of plastid, mitochondrial, and nuclear sequence per species. Relying on 16 fossil calibration points and three molecular dating methods, we show that Cupressaceae originated during the Triassic, when Pangea was intact. Vicariance between the two subfamilies, the Laurasian Cupressoideae and the Gondwanan Callitroideae, occurred around 153 Ma (124-183 Ma), when Gondwana and Laurasia were separating. Three further intercontinental disjunctions involving the Northern and Southern Hemisphere are coincidental with or immediately followed the breakup of Pangea.

Affective learning in adults with intellectual disability: an experiment using evaluative conditioning.

PubMed

Blanchette, I; Treillet, V; Davies, S R

2016-03-01

Evaluative conditioning is a form of affective learning in which initially neutral stimuli acquire an affective value through association with negative or positive stimuli. Recent research shows an important role for cognitive resources in this type of learning. This form of affective learning has rarely been studied in intellectual disability (ID). We examined evaluative conditioning in 16 adults with mild to moderate ID compared to age- and gender-matched control participants. Neutral shapes and symbols were repeatedly paired with positive, neutral or negative unconditioned stimuli (faces or International Affective Picture System images). There was also an extinction phase. There was significant acquisition of conditioning in both groups. Stimuli paired with positive images were evaluated more positively, and stimuli paired with negative images were evaluated more negatively. Post-extinction ratings however show that these novel affective associations were not maintained by individuals with ID as much as by individuals in the control group. We conclude that ID modulates some aspects of affective learning but not necessarily initial preference acquisition. © 2015 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.